CN111107848B - 一种含有酰胺类衍生物的药物组合物及其制备方法和应用 - Google Patents
一种含有酰胺类衍生物的药物组合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN111107848B CN111107848B CN201980004523.4A CN201980004523A CN111107848B CN 111107848 B CN111107848 B CN 111107848B CN 201980004523 A CN201980004523 A CN 201980004523A CN 111107848 B CN111107848 B CN 111107848B
- Authority
- CN
- China
- Prior art keywords
- group
- pharmaceutical composition
- alkyl
- pyridin
- imidazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 84
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 65
- 150000001408 amides Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 6
- 229940127254 ASK1 inhibitor Drugs 0.000 claims abstract description 5
- 239000003937 drug carrier Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 17
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 17
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 17
- 239000004480 active ingredient Substances 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 239000000725 suspension Substances 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 239000003981 vehicle Substances 0.000 claims description 9
- 239000003921 oil Substances 0.000 claims description 8
- 235000019198 oils Nutrition 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 239000003826 tablet Substances 0.000 claims description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 238000007918 intramuscular administration Methods 0.000 claims description 4
- 231100000252 nontoxic Toxicity 0.000 claims description 4
- 230000003000 nontoxic effect Effects 0.000 claims description 4
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000002480 mineral oil Substances 0.000 claims description 3
- 235000010446 mineral oil Nutrition 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 239000007764 o/w emulsion Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000006188 syrup Substances 0.000 claims description 3
- 235000020357 syrup Nutrition 0.000 claims description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 3
- 239000008158 vegetable oil Substances 0.000 claims description 3
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 2
- 239000007902 hard capsule Substances 0.000 claims description 2
- 229940102223 injectable solution Drugs 0.000 claims description 2
- 229940102213 injectable suspension Drugs 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 239000007901 soft capsule Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 206010061218 Inflammation Diseases 0.000 abstract description 5
- 230000004054 inflammatory process Effects 0.000 abstract description 5
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 2
- 230000001363 autoimmune Effects 0.000 abstract description 2
- -1 nitro, hydroxy Chemical group 0.000 description 253
- 125000000217 alkyl group Chemical group 0.000 description 192
- 125000000623 heterocyclic group Chemical group 0.000 description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
- 125000003545 alkoxy group Chemical group 0.000 description 113
- 125000001072 heteroaryl group Chemical group 0.000 description 112
- 125000003118 aryl group Chemical group 0.000 description 103
- 125000000753 cycloalkyl group Chemical group 0.000 description 80
- 229910052736 halogen Inorganic materials 0.000 description 76
- 150000002367 halogens Chemical class 0.000 description 76
- 238000005481 NMR spectroscopy Methods 0.000 description 66
- 125000004093 cyano group Chemical group *C#N 0.000 description 66
- 125000001424 substituent group Chemical group 0.000 description 64
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 63
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 59
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 59
- 238000006243 chemical reaction Methods 0.000 description 54
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 53
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 53
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 49
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 46
- 125000001188 haloalkyl group Chemical group 0.000 description 44
- 125000006413 ring segment Chemical group 0.000 description 44
- 229910052805 deuterium Inorganic materials 0.000 description 40
- 239000012074 organic phase Substances 0.000 description 38
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
- 125000003342 alkenyl group Chemical group 0.000 description 36
- 229910052757 nitrogen Inorganic materials 0.000 description 36
- 230000015572 biosynthetic process Effects 0.000 description 35
- 238000003786 synthesis reaction Methods 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 33
- 125000000304 alkynyl group Chemical group 0.000 description 32
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 29
- 125000004438 haloalkoxy group Chemical group 0.000 description 28
- 150000001975 deuterium Chemical group 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 26
- 229910052760 oxygen Inorganic materials 0.000 description 26
- 239000001301 oxygen Substances 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 25
- 125000005843 halogen group Chemical group 0.000 description 25
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 23
- 229920006395 saturated elastomer Polymers 0.000 description 23
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 22
- 239000012043 crude product Substances 0.000 description 21
- 125000004431 deuterium atom Chemical group 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 125000005842 heteroatom Chemical group 0.000 description 20
- 238000012360 testing method Methods 0.000 description 20
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 19
- 229960000583 acetic acid Drugs 0.000 description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- 239000003960 organic solvent Substances 0.000 description 18
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 18
- 125000000714 pyrimidinyl group Chemical group 0.000 description 18
- 125000000168 pyrrolyl group Chemical group 0.000 description 18
- 125000000335 thiazolyl group Chemical group 0.000 description 18
- 125000001544 thienyl group Chemical group 0.000 description 18
- 125000001425 triazolyl group Chemical group 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 17
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 17
- 125000002883 imidazolyl group Chemical group 0.000 description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 17
- 125000003226 pyrazolyl group Chemical group 0.000 description 17
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 125000002541 furyl group Chemical group 0.000 description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 16
- 125000002757 morpholinyl group Chemical group 0.000 description 16
- 125000002971 oxazolyl group Chemical group 0.000 description 16
- 125000004193 piperazinyl group Chemical group 0.000 description 16
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 16
- 125000003373 pyrazinyl group Chemical group 0.000 description 16
- 125000004076 pyridyl group Chemical group 0.000 description 16
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 16
- 125000003831 tetrazolyl group Chemical group 0.000 description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 16
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 15
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 15
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 15
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 15
- 125000002632 imidazolidinyl group Chemical group 0.000 description 15
- 125000003386 piperidinyl group Chemical group 0.000 description 15
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 15
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 15
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 15
- 210000004369 blood Anatomy 0.000 description 14
- 239000008280 blood Substances 0.000 description 14
- 238000000605 extraction Methods 0.000 description 14
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 102100033127 Mitogen-activated protein kinase kinase kinase 5 Human genes 0.000 description 13
- 125000003277 amino group Chemical group 0.000 description 13
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 13
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 13
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 13
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 13
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 13
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 13
- 101001018196 Homo sapiens Mitogen-activated protein kinase kinase kinase 5 Proteins 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 12
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 12
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 11
- GTLSATCTAXIGPQ-UHFFFAOYSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methylbenzoyl chloride Chemical compound CC1=C(C=C(C(Cl)=O)C(F)=C1)N1C=NC(=C1)C1CC1 GTLSATCTAXIGPQ-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- 229910052698 phosphorus Inorganic materials 0.000 description 9
- 239000011574 phosphorus Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-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
- 125000003282 alkyl amino group Chemical group 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 125000000000 cycloalkoxy group Chemical group 0.000 description 8
- 125000005366 cycloalkylthio group Chemical group 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000012362 glacial acetic acid Substances 0.000 description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 8
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 150000007942 carboxylates Chemical class 0.000 description 7
- 125000005345 deuteroalkyl group Chemical group 0.000 description 7
- 210000002381 plasma Anatomy 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical compound CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 102000001253 Protein Kinase Human genes 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 108060006633 protein kinase Proteins 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 4
- IFTHQZYTXKIHJQ-QGZVFWFLSA-N 5-(4-cyclopropylimidazol-1-yl)-N-[6-[(5S)-5-ethenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-2-fluoro-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@H]3C=C)C=1)F)C IFTHQZYTXKIHJQ-QGZVFWFLSA-N 0.000 description 4
- NFTRIBBBEKSTRA-UHFFFAOYSA-N CCCOC(C(OCCCF)(OCCF)OF)(C(OCC(OC)(OCC)Cl)(OCCl)Cl)OCF Chemical compound CCCOC(C(OCCCF)(OCCF)OF)(C(OCC(OC)(OCC)Cl)(OCCl)Cl)OCF NFTRIBBBEKSTRA-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 239000004530 micro-emulsion Substances 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- QMXPTUUFGSTIKK-RXMQYKEDSA-N (5r)-5-ethylpyrrolidin-2-one Chemical compound CC[C@@H]1CCC(=O)N1 QMXPTUUFGSTIKK-RXMQYKEDSA-N 0.000 description 3
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 3
- WCCCDMWRBVVYCQ-UHFFFAOYSA-N 2-bromo-1-cyclopropylethanone Chemical compound BrCC(=O)C1CC1 WCCCDMWRBVVYCQ-UHFFFAOYSA-N 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- YUFPSBJEZFBQQK-OAHLLOKOSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound C[C@@H]1CCC2=NN=C(N12)C1=CC=CC(NC(=O)C2=C(F)C=C(C)C(=C2)N2C=NC(=C2)C2CC2)=N1 YUFPSBJEZFBQQK-OAHLLOKOSA-N 0.000 description 3
- VKTHZDRBOQMORA-FQEVSTJZSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@H]3C(F)(F)F)C=1)F)C VKTHZDRBOQMORA-FQEVSTJZSA-N 0.000 description 3
- TXYJSZSDDBZVTB-CQSZACIVSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(6R)-6-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound [C@H]1(C)CN2C(=NN=C2C2=NC(NC(=O)C3=CC(N4C=C(C5CC5)N=C4)=C(C=C3F)C)=CC=C2)C1 TXYJSZSDDBZVTB-CQSZACIVSA-N 0.000 description 3
- AXTUTVOXCLUJMK-UHFFFAOYSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methylbenzoic acid;hydrochloride Chemical compound Cl.CC1=CC(F)=C(C(O)=O)C=C1N1C=C(C2CC2)N=C1 AXTUTVOXCLUJMK-UHFFFAOYSA-N 0.000 description 3
- VWSFOEHQKFAAGN-UHFFFAOYSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methylbenzonitrile Chemical compound CC1=CC(F)=C(C#N)C=C1N1C=C(C2CC2)N=C1 VWSFOEHQKFAAGN-UHFFFAOYSA-N 0.000 description 3
- WCFARSVAAYDNPA-INIZCTEOSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-N-[6-[(5S)-5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-4-methylbenzamide Chemical compound [C@H]1(CF)N2C(CC1)=NN=C2C1=NC(NC(=O)C2=CC(=C(C)C=C2F)N2C=C(C3CC3)N=C2)=CC=C1 WCFARSVAAYDNPA-INIZCTEOSA-N 0.000 description 3
- OSWLXBMPXPDDPY-QGZVFWFLSA-N 5-(4-cyclopropylimidazol-1-yl)-N-[6-[(5R)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-2-fluoro-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@H]3CC)C=1)F)C OSWLXBMPXPDDPY-QGZVFWFLSA-N 0.000 description 3
- SCZXIFDUERAPNF-QGZVFWFLSA-N 5-(4-cyclopropylimidazol-1-yl)-N-[6-[(5S)-5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-2-fluoro-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@H]3C#C)C=1)F)C SCZXIFDUERAPNF-QGZVFWFLSA-N 0.000 description 3
- GPWZGVIWTGDEMY-UHFFFAOYSA-N 5-amino-2-fluoro-4-methylbenzonitrile Chemical compound CC1=CC(F)=C(C#N)C=C1N GPWZGVIWTGDEMY-UHFFFAOYSA-N 0.000 description 3
- UHKYWOGOQWXFHU-UHFFFAOYSA-N 6-(4-cyclopropylimidazol-1-yl)-5-methyl-2,3-dihydroisoindol-1-one Chemical compound C1(CC1)C=1N=CN(C=1)C1=C(C=C2CNC(C2=C1)=O)C UHKYWOGOQWXFHU-UHFFFAOYSA-N 0.000 description 3
- BEYCFGZTCWKJKZ-UHFFFAOYSA-N 6-amino-5-methyl-2,3-dihydroisoindol-1-one Chemical compound C1=C(N)C(C)=CC2=C1C(=O)NC2 BEYCFGZTCWKJKZ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 101100455868 Arabidopsis thaliana MKK2 gene Proteins 0.000 description 3
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 3
- 206010053567 Coagulopathies Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- ZCXMYVIYNFVVPN-KRWDZBQOSA-N N-[6-[(5S)-5-(cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methylbenzamide Chemical compound [C@H]1(CC#N)N2C(CC1)=NN=C2C1=NC(NC(=O)C2=CC(=C(C)C=C2F)N2C=C(C3CC3)N=C2)=CC=C1 ZCXMYVIYNFVVPN-KRWDZBQOSA-N 0.000 description 3
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 238000004820 blood count Methods 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 230000035602 clotting Effects 0.000 description 3
- 230000002354 daily effect Effects 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- IESIARKLRXKFTG-ZCFIWIBFSA-N (2R)-2-ethyl-5-methoxy-3,4-dihydro-2H-pyrrole Chemical compound C(C)[C@H]1N=C(CC1)OC IESIARKLRXKFTG-ZCFIWIBFSA-N 0.000 description 2
- PLKWTXTXIRJHKF-RXMQYKEDSA-N (2R)-5-methoxy-2-methyl-3,4-dihydro-2H-pyrrole Chemical compound COC1=N[C@H](C)CC1 PLKWTXTXIRJHKF-RXMQYKEDSA-N 0.000 description 2
- PDYFGMILJRLZDE-YFKPBYRVSA-N (2S)-2-(fluoromethyl)-5-methoxy-3,4-dihydro-2H-pyrrole Chemical compound FC[C@H]1N=C(CC1)OC PDYFGMILJRLZDE-YFKPBYRVSA-N 0.000 description 2
- UHHFTIRMMFWKTB-ZCFIWIBFSA-N (2S)-2-ethenyl-5-methoxy-3,4-dihydro-2H-pyrrole Chemical compound COC=1CC[C@H](N=1)C=C UHHFTIRMMFWKTB-ZCFIWIBFSA-N 0.000 description 2
- XJILDRVUEWYRSF-BYPYZUCNSA-N (2S)-5-methoxy-2-(trifluoromethyl)-3,4-dihydro-2H-pyrrole Chemical compound COC=1CC[C@H](N=1)C(F)(F)F XJILDRVUEWYRSF-BYPYZUCNSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- OYVDXEVJHXWJAE-RXMQYKEDSA-N (5s)-5-ethenylpyrrolidin-2-one Chemical compound C=C[C@@H]1CCC(=O)N1 OYVDXEVJHXWJAE-RXMQYKEDSA-N 0.000 description 2
- ODCJSCFWGWZDMF-RXMQYKEDSA-N (5s)-5-ethynylpyrrolidin-2-one Chemical compound O=C1CC[C@@H](C#C)N1 ODCJSCFWGWZDMF-RXMQYKEDSA-N 0.000 description 2
- HXFYXLLVIVSPLT-UHFFFAOYSA-N (6-methylpyridin-2-yl)methanamine Chemical compound CC1=CC=CC(CN)=N1 HXFYXLLVIVSPLT-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- HPIUIKAAIWCCCC-OAHLLOKOSA-N 2-chloro-5-(4-cyclopropylimidazol-1-yl)-4-methyl-N-[6-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound [C@H]1(C)N2C(CC1)=NN=C2C1=NC(NC(=O)C2=CC(=C(C)C=C2Cl)N2C=C(C3CC3)N=C2)=CC=C1 HPIUIKAAIWCCCC-OAHLLOKOSA-N 0.000 description 2
- SHBDCIKKQVCTNP-UHFFFAOYSA-N 2-fluoro-4-methyl-5-(4-propan-2-ylimidazol-1-yl)-N-(6-spiro[6,7-dihydropyrrolo[2,1-c][1,2,4]triazole-5,1'-cyclopropane]-3-ylpyridin-2-yl)benzamide Chemical compound N=1N=C(N2C=1CCC21CC1)C1=CC=CC(=N1)NC(C1=C(C=C(C(=C1)N1C=NC(=C1)C(C)C)C)F)=O SHBDCIKKQVCTNP-UHFFFAOYSA-N 0.000 description 2
- YDBRVFWQGCMUTC-MRXNPFEDSA-N 2-fluoro-4-methyl-N-[6-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-5-(4-propan-2-ylimidazol-1-yl)benzamide Chemical compound [C@H]1(C)N2C(CC1)=NN=C2C1=NC(NC(=O)C2=CC(=C(C)C=C2F)N2C=C(C(C)C)N=C2)=CC=C1 YDBRVFWQGCMUTC-MRXNPFEDSA-N 0.000 description 2
- YDBRVFWQGCMUTC-INIZCTEOSA-N 2-fluoro-4-methyl-N-[6-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-5-(4-propan-2-ylimidazol-1-yl)benzamide Chemical compound [C@H]1(N2C(CC1)=NN=C2C1=NC(NC(=O)C2=CC(=C(C)C=C2F)N2C=C(C(C)C)N=C2)=CC=C1)C YDBRVFWQGCMUTC-INIZCTEOSA-N 0.000 description 2
- XUVUTIQUJXDEJD-QGZVFWFLSA-N 2-fluoro-N-[6-[(5R)-5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-4-methyl-5-(4-propan-2-ylimidazol-1-yl)benzamide Chemical compound FC1=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@@H]3COC)C=C(C(=C1)C)N1C=NC(=C1)C(C)C XUVUTIQUJXDEJD-QGZVFWFLSA-N 0.000 description 2
- XUVUTIQUJXDEJD-KRWDZBQOSA-N 2-fluoro-N-[6-[(5S)-5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-4-methyl-5-(4-propan-2-ylimidazol-1-yl)benzamide Chemical compound FC1=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@H]3COC)C=C(C(=C1)C)N1C=NC(=C1)C(C)C XUVUTIQUJXDEJD-KRWDZBQOSA-N 0.000 description 2
- KHCRYOQAIDGATM-UHFFFAOYSA-N 3-(6-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole Chemical compound ClC1=CC=CC(=N1)C=1N2C(=NN=1)CCC2 KHCRYOQAIDGATM-UHFFFAOYSA-N 0.000 description 2
- MMJYUJRFIWPCHG-UHFFFAOYSA-N 4-(4-cyclopropylimidazol-1-yl)-N-[3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl]pyridine-2-carboxamide Chemical compound C1N2C(CC1)=NN=C2C1=CC=CC(NC(=O)C2=CC(N3C=C(C4CC4)N=C3)=CC=N2)=C1 MMJYUJRFIWPCHG-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IQYZSEJHNJSVSK-UHFFFAOYSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-(6-spiro[5,7-dihydropyrrolo[2,1-c][1,2,4]triazole-6,1'-cyclopropane]-3-ylpyridin-2-yl)benzamide Chemical compound N=1N=C(N2C=1CC1(C2)CC1)C1=CC=CC(=N1)NC(C1=C(C=C(C(=C1)N1C=NC(=C1)C1CC1)C)F)=O IQYZSEJHNJSVSK-UHFFFAOYSA-N 0.000 description 2
- TWPXIFUWERRIJW-UHFFFAOYSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-(6-spiro[6,7-dihydropyrrolo[2,1-c][1,2,4]triazole-5,1'-cyclopropane]-3-ylpyridin-2-yl)benzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CCC32CC2)C=1)F)C TWPXIFUWERRIJW-UHFFFAOYSA-N 0.000 description 2
- TXYJSZSDDBZVTB-UHFFFAOYSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-(6-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl]benzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC(C3)C)C=1)F)C TXYJSZSDDBZVTB-UHFFFAOYSA-N 0.000 description 2
- NKOCUDWFXRYOJD-JOCHJYFZSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5R)-5-propan-2-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@@H]3C(C)C)C=1)F)C NKOCUDWFXRYOJD-JOCHJYFZSA-N 0.000 description 2
- RPYLMQHUIHSMPX-GOSISDBHSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5R)-5-propyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound C(C[C@H]1N2C(=NN=C2C2=NC(NC(=O)C3=CC(=C(C)C=C3F)N3C=C(C4CC4)N=C3)=CC=C2)CC1)C RPYLMQHUIHSMPX-GOSISDBHSA-N 0.000 description 2
- YUFPSBJEZFBQQK-HNNXBMFYSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound C[C@H]1CCC2=NN=C(N12)C1=CC=CC(NC(=O)C2=C(F)C=C(C)C(=C2)N2C=NC(=C2)C2CC2)=N1 YUFPSBJEZFBQQK-HNNXBMFYSA-N 0.000 description 2
- NKOCUDWFXRYOJD-QFIPXVFZSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5S)-5-propan-2-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@H]3C(C)C)C=1)F)C NKOCUDWFXRYOJD-QFIPXVFZSA-N 0.000 description 2
- RPYLMQHUIHSMPX-SFHVURJKSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5S)-5-propyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound C(C)C[C@@H]1N2C(CC1)=NN=C2C1=NC(NC(=O)C2=CC(=C(C)C=C2F)N2C=C(C3CC3)N=C2)=CC=C1 RPYLMQHUIHSMPX-SFHVURJKSA-N 0.000 description 2
- YAJUIJOIPIHPLP-UHFFFAOYSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-N-[6-(6-methoxy-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl]-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC(C3)OC)C=1)F)C YAJUIJOIPIHPLP-UHFFFAOYSA-N 0.000 description 2
- WCFARSVAAYDNPA-MRXNPFEDSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-N-[6-[(5R)-5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@@H]3CF)C=1)F)C WCFARSVAAYDNPA-MRXNPFEDSA-N 0.000 description 2
- WFIWXUPPCUUYEK-QGZVFWFLSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-N-[6-[(5R)-5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@@H]3COC)C=1)F)C WFIWXUPPCUUYEK-QGZVFWFLSA-N 0.000 description 2
- SSCAWBYGCIZRKP-OPAMFIHVSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-N-[6-[(5R)-5-[(1R)-1-methoxyethyl]-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@@H]3[C@@H](C)OC)C=1)F)C SSCAWBYGCIZRKP-OPAMFIHVSA-N 0.000 description 2
- ZXJMXEDWRSRATJ-INIZCTEOSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-N-[6-[(5S)-5-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@H]3CO)C=1)F)C ZXJMXEDWRSRATJ-INIZCTEOSA-N 0.000 description 2
- WFIWXUPPCUUYEK-KRWDZBQOSA-N 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-N-[6-[(5S)-5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@H]3COC)C=1)F)C WFIWXUPPCUUYEK-KRWDZBQOSA-N 0.000 description 2
- AAGPNUMTWORZED-UHFFFAOYSA-N 5-(4-cyclopropylimidazol-1-yl)-N-[6-(5,5-dimethyl-6,7-dihydropyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl]-2-fluoro-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CCC3(C)C)C=1)F)C AAGPNUMTWORZED-UHFFFAOYSA-N 0.000 description 2
- SCZXIFDUERAPNF-UHFFFAOYSA-N 5-(4-cyclopropylimidazol-1-yl)-N-[6-(5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl]-2-fluoro-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CCC3C#C)C=1)F)C SCZXIFDUERAPNF-UHFFFAOYSA-N 0.000 description 2
- RKJGNIBDQTUASB-UHFFFAOYSA-N 5-(4-cyclopropylimidazol-1-yl)-N-[6-(6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl]-2-fluoro-4-methylbenzamide Chemical compound CC1=CC(F)=C(C=C1N1C=NC(=C1)C1CC1)C(=O)NC1=NC(=CC=C1)C1=NN=C2COCCN12 RKJGNIBDQTUASB-UHFFFAOYSA-N 0.000 description 2
- SCZXIFDUERAPNF-KRWDZBQOSA-N 5-(4-cyclopropylimidazol-1-yl)-N-[6-[(5R)-5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-2-fluoro-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@@H]3C#C)C=1)F)C SCZXIFDUERAPNF-KRWDZBQOSA-N 0.000 description 2
- OSWLXBMPXPDDPY-KRWDZBQOSA-N 5-(4-cyclopropylimidazol-1-yl)-N-[6-[(5S)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-2-fluoro-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC[C@@H]3CC)C=1)F)C OSWLXBMPXPDDPY-KRWDZBQOSA-N 0.000 description 2
- FKJTZQXQIYQWIE-MRXNPFEDSA-N 5-(4-tert-butylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound [C@H]1(C)N2C(CC1)=NN=C2C1=NC(NC(=O)C2=CC(=C(C)C=C2F)N2C=C(C(C)(C)C)N=C2)=CC=C1 FKJTZQXQIYQWIE-MRXNPFEDSA-N 0.000 description 2
- FKJTZQXQIYQWIE-INIZCTEOSA-N 5-(4-tert-butylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]benzamide Chemical compound [C@H]1(N2C(CC1)=NN=C2C1=NC(NC(=O)C2=CC(=C(C)C=C2F)N2C=C(C(C)(C)C)N=C2)=CC=C1)C FKJTZQXQIYQWIE-INIZCTEOSA-N 0.000 description 2
- FGNHHHJOTZKDEM-QGZVFWFLSA-N 5-(4-tert-butylimidazol-1-yl)-2-fluoro-N-[6-[(5R)-5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-4-methylbenzamide Chemical compound N12C(=NN=C2C2=NC(NC(=O)C3=CC(=C(C)C=C3F)N3C=C(C(C)(C)C)N=C3)=CC=C2)CC[C@@H]1COC FGNHHHJOTZKDEM-QGZVFWFLSA-N 0.000 description 2
- FGNHHHJOTZKDEM-KRWDZBQOSA-N 5-(4-tert-butylimidazol-1-yl)-2-fluoro-N-[6-[(5S)-5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-4-methylbenzamide Chemical compound [C@H]1(COC)N2C(CC1)=NN=C2C1=NC(NC(=O)C2=CC(=C(C)C=C2F)N2C=C(C(C)(C)C)N=C2)=CC=C1 FGNHHHJOTZKDEM-KRWDZBQOSA-N 0.000 description 2
- YSWOWAIEZYDOGB-UHFFFAOYSA-N 5-(5-cyclopropyl-2-sulfanylidene-1h-imidazol-3-yl)-2-fluoro-4-methylbenzonitrile Chemical compound CC1=CC(F)=C(C#N)C=C1N1C(S)=NC(C2CC2)=C1 YSWOWAIEZYDOGB-UHFFFAOYSA-N 0.000 description 2
- XBXVVUBUVBAYDE-UHFFFAOYSA-N 5-methoxy-2,2-dimethyl-3,4-dihydropyrrole Chemical compound COC=1CCC(N=1)(C)C XBXVVUBUVBAYDE-UHFFFAOYSA-N 0.000 description 2
- SGOXAEOBENHBPG-UHFFFAOYSA-N 6-(4-cyclopropylimidazol-1-yl)-5-methyl-2-(6-spiro[6,7-dihydropyrrolo[2,1-c][1,2,4]triazole-5,1'-cyclopropane]-3-ylpyridin-2-yl)-3H-isoindol-1-one Chemical compound C1(CC1)C=1N=CN(C=1)C1=C(C=C2CN(C(C2=C1)=O)C1=NC(=CC=C1)C=1N2C(=NN=1)CCC21CC1)C SGOXAEOBENHBPG-UHFFFAOYSA-N 0.000 description 2
- WWPYPHJNTAXCEL-NRFANRHFSA-N 6-(4-cyclopropylimidazol-1-yl)-5-methyl-2-[6-[(5S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-3H-isoindol-1-one Chemical compound C1(CC1)C=1N=CN(C=1)C1=C(C=C2CN(C(C2=C1)=O)C1=NC(=CC=C1)C=1N2C(=NN=1)CC[C@H]2C(F)(F)F)C WWPYPHJNTAXCEL-NRFANRHFSA-N 0.000 description 2
- ZHJRMXGGDDMYNE-UHFFFAOYSA-N 6-(5,5-dimethyl-6,7-dihydropyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine Chemical compound CC1(CCC2=NN=C(N21)C1=CC=CC(=N1)N)C ZHJRMXGGDDMYNE-UHFFFAOYSA-N 0.000 description 2
- KZOSXQSSQOPAJJ-UHFFFAOYSA-N 6-(6,7-dihydro-5h-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-amine Chemical compound NC1=CC=CC(C=2N3CCCC3=NN=2)=N1 KZOSXQSSQOPAJJ-UHFFFAOYSA-N 0.000 description 2
- JZAGPWXJYKXGGF-MRVPVSSYSA-N 6-[(5R)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-amine Chemical compound C(C)[C@@H]1CCC2=NN=C(N21)C1=CC=CC(=N1)N JZAGPWXJYKXGGF-MRVPVSSYSA-N 0.000 description 2
- DRKWJUFJOAHJBK-SSDOTTSWSA-N 6-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-amine Chemical compound C[C@@H]1CCC2=NN=C(N21)C1=CC=CC(=N1)N DRKWJUFJOAHJBK-SSDOTTSWSA-N 0.000 description 2
- WAQBMIUKNIJNPE-ZETCQYMHSA-N 6-[(5S)-5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-amine Chemical compound FC[C@@H]1CCC2=NN=C(N21)C1=CC=CC(=N1)N WAQBMIUKNIJNPE-ZETCQYMHSA-N 0.000 description 2
- KESXXITXWHZRGG-ZETCQYMHSA-N 6-[(5S)-5-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-amine Chemical compound [C@H]1(C(F)(F)F)N2C(CC1)=NN=C2C1=NC(=CC=C1)N KESXXITXWHZRGG-ZETCQYMHSA-N 0.000 description 2
- ULZNBQNLVDZTLD-MRVPVSSYSA-N 6-[(5S)-5-ethenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-amine Chemical compound C(=C)[C@@H]1CCC2=NN=C(N21)C1=CC=CC(=N1)N ULZNBQNLVDZTLD-MRVPVSSYSA-N 0.000 description 2
- CNDIBPJGGKWJFE-MRVPVSSYSA-N 6-[(5S)-5-ethynyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-amine Chemical compound C#C[C@H]1N2C(CC1)=NN=C2C1=NC(=CC=C1)N CNDIBPJGGKWJFE-MRVPVSSYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 2
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 2
- YOMHFOWAGRYZIE-YFKPBYRVSA-N C(=O)=C1CC[C@H](N1)C=O Chemical compound C(=O)=C1CC[C@H](N1)C=O YOMHFOWAGRYZIE-YFKPBYRVSA-N 0.000 description 2
- ISDHIUUCDRCWGK-UHFFFAOYSA-N C1(CC1)C(CNC=1C(=CC(=C(C#N)C=1)F)C)=C=O Chemical compound C1(CC1)C(CNC=1C(=CC(=C(C#N)C=1)F)C)=C=O ISDHIUUCDRCWGK-UHFFFAOYSA-N 0.000 description 2
- ICANFQLMRXWPRI-QMMMGPOBSA-N CC(C)(C)OC(N([C@@H](CC1)C=O)C1=C=O)=O Chemical compound CC(C)(C)OC(N([C@@H](CC1)C=O)C1=C=O)=O ICANFQLMRXWPRI-QMMMGPOBSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- MJBQUJSHJXMPGD-UHFFFAOYSA-N N-[6-(6-cyclopropyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl]-5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methylbenzamide Chemical compound C1(CC1)C=1N=CN(C=1)C=1C(=CC(=C(C(=O)NC2=NC(=CC=C2)C=2N3C(=NN=2)CC(C3)C2CC2)C=1)F)C MJBQUJSHJXMPGD-UHFFFAOYSA-N 0.000 description 2
- AGHQVTGTIPJYHK-UHFFFAOYSA-N N-[6-(7-acetyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl]-5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methylbenzamide Chemical compound C(=O)(N1CCN2C(=NN=C2C2=NC(NC(=O)C3=CC(=C(C)C=C3F)N3C=C(C4CC4)N=C3)=CC=C2)C1)C AGHQVTGTIPJYHK-UHFFFAOYSA-N 0.000 description 2
- ONABAILNPLQYHX-MRXNPFEDSA-N N-[6-[(5R)-5-cyano-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methylbenzamide Chemical compound C(#N)[C@H]1CCC2=NN=C(N21)C1=CC=CC(=N1)NC(C1=C(C=C(C(=C1)N1C=NC(=C1)C1CC1)C)F)=O ONABAILNPLQYHX-MRXNPFEDSA-N 0.000 description 2
- ONABAILNPLQYHX-INIZCTEOSA-N N-[6-[(5S)-5-cyano-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methylbenzamide Chemical compound C(#N)[C@@H]1CCC2=NN=C(N21)C1=CC=CC(=N1)NC(C1=C(C=C(C(=C1)N1C=NC(=C1)C1CC1)C)F)=O ONABAILNPLQYHX-INIZCTEOSA-N 0.000 description 2
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 2
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 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 2
- 239000002253 acid Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 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 2
- 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 2
- 230000034994 death Effects 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000006005 fluoroethoxy group Chemical group 0.000 description 2
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 2
- HQVFCQRVQFYGRJ-UHFFFAOYSA-N formic acid;hydrate Chemical compound O.OC=O HQVFCQRVQFYGRJ-UHFFFAOYSA-N 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000004072 lung Anatomy 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
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 231100000682 maximum tolerated dose Toxicity 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- KPMCXWQCZYLVSI-UHFFFAOYSA-N methyl 5-amino-2-cyano-4-methylbenzoate Chemical compound CC1=C(N)C=C(C(=O)OC)C(C#N)=C1 KPMCXWQCZYLVSI-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000010414 supernatant solution Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- KIXRQZRKBFYCTK-ZCFIWIBFSA-N (2S)-2-ethynyl-5-methoxy-3,4-dihydro-2H-pyrrole Chemical compound C(#C)[C@H]1N=C(CC1)OC KIXRQZRKBFYCTK-ZCFIWIBFSA-N 0.000 description 1
- 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 1
- IHKAGESSVVOIIU-UHFFFAOYSA-N (3-ethoxy-3-methoxypropyl) hypofluorite Chemical compound CCOC(OC)CCOF IHKAGESSVVOIIU-UHFFFAOYSA-N 0.000 description 1
- YVIVRJLWYJGJTJ-SCSAIBSYSA-N (5r)-5-methylpyrrolidin-2-one Chemical compound C[C@@H]1CCC(=O)N1 YVIVRJLWYJGJTJ-SCSAIBSYSA-N 0.000 description 1
- WQNMHLGUIXQTED-BYPYZUCNSA-N (5s)-5-(fluoromethyl)pyrrolidin-2-one Chemical compound FC[C@@H]1CCC(=O)N1 WQNMHLGUIXQTED-BYPYZUCNSA-N 0.000 description 1
- HOBJEFOCIRXQKH-BYPYZUCNSA-N (5s)-5-(hydroxymethyl)pyrrolidin-2-one Chemical compound OC[C@@H]1CCC(=O)N1 HOBJEFOCIRXQKH-BYPYZUCNSA-N 0.000 description 1
- BKONNPBZAYHNOV-VKHMYHEASA-N (5s)-5-(trifluoromethyl)pyrrolidin-2-one Chemical compound FC(F)(F)[C@@H]1CCC(=O)N1 BKONNPBZAYHNOV-VKHMYHEASA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products 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
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 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
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- HORQAOAYAYGIBM-UHFFFAOYSA-N 2,4-dinitrophenylhydrazine Chemical compound NNC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O HORQAOAYAYGIBM-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- PTPOZUPHOHBFPZ-UHFFFAOYSA-N 2-chloro-6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridine Chemical compound CC(C)N1C=NN=C1C1=NC(Cl)=CC=C1 PTPOZUPHOHBFPZ-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- UUTGCNVYKLQLRV-UHFFFAOYSA-N 5,5-dimethylpyrrolidin-2-one Chemical compound CC1(C)CCC(=O)N1 UUTGCNVYKLQLRV-UHFFFAOYSA-N 0.000 description 1
- DNCLVDGUXUSPTL-UHFFFAOYSA-N 5-bromo-4-fluoro-2-methylaniline Chemical compound CC1=CC(F)=C(Br)C=C1N DNCLVDGUXUSPTL-UHFFFAOYSA-N 0.000 description 1
- QYGNDKJRRNVSEC-UHFFFAOYSA-N 5-methoxy-3,4-dihydro-2h-pyrrole Chemical compound COC1=NCCC1 QYGNDKJRRNVSEC-UHFFFAOYSA-N 0.000 description 1
- VWWHNILJLQBJGG-UHFFFAOYSA-N 5-methoxy-4-azaspiro[2.4]hept-4-ene Chemical compound COC1=NC2(CC2)CC1 VWWHNILJLQBJGG-UHFFFAOYSA-N 0.000 description 1
- SGGRDXQQEBLHGJ-UHFFFAOYSA-N 6-(5-cyclopropyl-2-sulfanylidene-1H-imidazol-3-yl)-5-methyl-2,3-dihydroisoindol-1-one Chemical compound C1(CC1)C=1N=C(N(C=1)C1=C(C=C2CNC(C2=C1)=O)C)S SGGRDXQQEBLHGJ-UHFFFAOYSA-N 0.000 description 1
- QXIXLAPXTSLEAB-UHFFFAOYSA-N 6-spiro[6,7-dihydropyrrolo[2,1-c][1,2,4]triazole-5,1'-cyclopropane]-3-ylpyridin-2-amine Chemical compound N=1N=C(N2C=1CCC21CC1)C1=CC=CC(=N1)N QXIXLAPXTSLEAB-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- YGEINXLWISRQTG-YFKPBYRVSA-N C(=O)=C1CC[C@H](N1)C(=O)O Chemical compound C(=O)=C1CC[C@H](N1)C(=O)O YGEINXLWISRQTG-YFKPBYRVSA-N 0.000 description 1
- KWLHCQSZNNOZIN-JTQLQIEISA-N C(C)(C)(C)OC(=O)N1[C@@H](CCC1=C=O)C(=O)SCC Chemical compound C(C)(C)(C)OC(=O)N1[C@@H](CCC1=C=O)C(=O)SCC KWLHCQSZNNOZIN-JTQLQIEISA-N 0.000 description 1
- TTWAAFZBZIIBLQ-LLVKDONJSA-N C(C)(C)(C)[C@]1(N(C(CC1)=C=O)C(=O)O)C=O Chemical compound C(C)(C)(C)[C@]1(N(C(CC1)=C=O)C(=O)O)C=O TTWAAFZBZIIBLQ-LLVKDONJSA-N 0.000 description 1
- SUESJIYSJYWBRD-UHFFFAOYSA-N C1(CC1)C(CNC1=C(C=C2CNC(C2=C1)=O)C)=C=O Chemical compound C1(CC1)C(CNC1=C(C=C2CNC(C2=C1)=O)C)=C=O SUESJIYSJYWBRD-UHFFFAOYSA-N 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 101710084687 Cyclin-dependent kinase 2 homolog Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 102100023275 Dual specificity mitogen-activated protein kinase kinase 3 Human genes 0.000 description 1
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 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
- 239000005977 Ethylene Substances 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 101001115394 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 3 Proteins 0.000 description 1
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 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 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 108010075639 MAP Kinase Kinase Kinase 5 Proteins 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101100288142 Mus musculus Klkb1 gene Proteins 0.000 description 1
- ZCXMYVIYNFVVPN-QGZVFWFLSA-N N-[6-[(5R)-5-(cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl]-5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methylbenzamide Chemical compound C1CC=2N([C@H]1CC#N)C(C1=NC(NC(=O)C3=CC(=C(C)C=C3F)N3C=C(C4CC4)N=C3)=CC=C1)=NN=2 ZCXMYVIYNFVVPN-QGZVFWFLSA-N 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 101100288143 Rattus norvegicus Klkb1 gene Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- SYKNUAWMBRIEKB-UHFFFAOYSA-N [Cl].[Br] Chemical compound [Cl].[Br] SYKNUAWMBRIEKB-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 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
- 230000008901 benefit Effects 0.000 description 1
- DNOFIHGTRCZHPH-UHFFFAOYSA-N benzotriazol-4-one Chemical compound O=C1C=CC=C2N=NN=C12 DNOFIHGTRCZHPH-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 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
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000006011 chloroethoxy group Chemical group 0.000 description 1
- 125000004651 chloromethoxy group Chemical group ClCO* 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 238000004163 cytometry Methods 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- SGDINNZGYDHHKM-UHFFFAOYSA-N dilithium;trimethylsilylazanide Chemical compound [Li+].[Li+].C[Si](C)(C)[NH-].C[Si](C)(C)[NH-] SGDINNZGYDHHKM-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- WZHKDGJSXCTSCK-UHFFFAOYSA-N hept-3-ene Chemical compound CCCC=CCC WZHKDGJSXCTSCK-UHFFFAOYSA-N 0.000 description 1
- NGAZZOYFWWSOGK-UHFFFAOYSA-N heptan-3-one Chemical compound CCCCC(=O)CC NGAZZOYFWWSOGK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 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
- 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
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 235000020938 metabolic status Nutrition 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- YZLNWLHJRDAYTM-UHFFFAOYSA-N methyl 5-amino-2-bromo-4-methylbenzoate Chemical compound COC(=O)C1=CC(N)=C(C)C=C1Br YZLNWLHJRDAYTM-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 239000011259 mixed solution Substances 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
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000003805 procoagulant Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 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
- 229910001467 sodium calcium phosphate Inorganic materials 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
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000008791 toxic response Effects 0.000 description 1
- 231100000607 toxicokinetics Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2018109097922 | 2018-08-10 | ||
CN201810909792 | 2018-08-10 | ||
PCT/CN2019/099971 WO2020030107A1 (fr) | 2018-08-10 | 2019-08-09 | Composition pharmaceutique contenant des dérivés amides, son procédé de préparation et application associée |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111107848A CN111107848A (zh) | 2020-05-05 |
CN111107848B true CN111107848B (zh) | 2023-05-23 |
Family
ID=69414002
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980004523.4A Active CN111107848B (zh) | 2018-08-10 | 2019-08-09 | 一种含有酰胺类衍生物的药物组合物及其制备方法和应用 |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN111107848B (fr) |
TW (1) | TW202012412A (fr) |
WO (1) | WO2020030107A1 (fr) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3825315B1 (fr) * | 2018-07-20 | 2022-08-31 | Fujian Akeylink Biotechnology Co., Ltd. | Forme cristalline utilisée en tant qu'inhibiteur d'ask1, son procédé de préparation et son utilisation |
CN110577533B (zh) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用 |
CN110577534B (zh) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用 |
CN110577540B (zh) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用 |
CN110577537B (zh) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用 |
CN110577538B (zh) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用 |
CN110577535B (zh) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用 |
CN110577536B (zh) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用 |
CN110577541B (zh) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用 |
CN110577539B (zh) * | 2019-07-16 | 2021-07-23 | 广州安岩仁医药科技有限公司 | 苯甲酰氨基吡啶衍生物的盐及其在药物中的应用 |
CN113831323A (zh) * | 2020-06-24 | 2021-12-24 | 武汉人福创新药物研发中心有限公司 | 芳杂环酰胺类化合物及其用途 |
CN115894404B (zh) * | 2021-09-22 | 2024-07-16 | 杭州天玑济世生物科技有限公司 | 一类具有萘胺结构的小分子化合物及其应用 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI598347B (zh) * | 2009-07-13 | 2017-09-11 | 基利科學股份有限公司 | 調節細胞凋亡信號之激酶的抑制劑 |
UY35212A (es) * | 2012-12-21 | 2014-06-30 | Gilead Sciences Inc | Inhibidores de la quinasa que regula la señal de la apoptosis |
TW201618781A (zh) * | 2014-08-13 | 2016-06-01 | 吉李德科學股份有限公司 | 治療肺高血壓之方法 |
US10787435B2 (en) * | 2017-01-22 | 2020-09-29 | Fuijan Cosunter Pharmaceutical Co. Ltd. | ASK1 inhibitor and preparation method and use thereof |
SG11201906579UA (en) * | 2017-01-22 | 2019-08-27 | Fujian Cosunter Pharmaceutical Co Ltd | Pyridine derivative as ask1 inhibitor and preparation method and use thereof |
WO2018151830A1 (fr) * | 2017-02-17 | 2018-08-23 | Fronthera U.S. Pharmaceuticals Llc | Inhibiteurs de kinase de régulation du signal apoptotique à base de pyridinyle |
TW201833108A (zh) * | 2017-03-03 | 2018-09-16 | 大陸商江蘇豪森藥業集團有限公司 | 醯胺類衍生物抑制劑及其製備方法和應用 |
WO2018233553A1 (fr) * | 2017-06-19 | 2018-12-27 | 广东东阳光药业有限公司 | Composé bicyclique fusionné et son utilisation en médecine |
CN109400625B (zh) * | 2017-08-17 | 2021-11-12 | 广东东阳光药业有限公司 | 稠合双环类化合物及其在药物中的应用 |
-
2019
- 2019-08-09 WO PCT/CN2019/099971 patent/WO2020030107A1/fr active Application Filing
- 2019-08-09 CN CN201980004523.4A patent/CN111107848B/zh active Active
- 2019-08-12 TW TW108128847A patent/TW202012412A/zh unknown
Also Published As
Publication number | Publication date |
---|---|
WO2020030107A1 (fr) | 2020-02-13 |
TW202012412A (zh) | 2020-04-01 |
CN111107848A (zh) | 2020-05-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111107848B (zh) | 一种含有酰胺类衍生物的药物组合物及其制备方法和应用 | |
CN109983007B (zh) | 酰胺类衍生物抑制剂及其制备方法和应用 | |
CN111295384B (zh) | 双环类衍生物抑制剂、其制备方法和应用 | |
TWI765908B (zh) | 苯並咪唑類化合物激酶抑制劑及其製備方法和應用 | |
CN115884969A (zh) | 稠合咪唑类衍生物、其制备方法及其在医药上的应用 | |
EP3919489A1 (fr) | Composés cycliques aromatiques ou cycliques hétéroaromatiques, procédé de préparation correspondant et utilisation médicale associée | |
WO2021228173A1 (fr) | Composés cycliques condensés du type azépine et utilisations médicales associées | |
CN113286796B (zh) | 喜树碱衍生物及其水溶性前药、包含其的药物组合物及其制备方法和用途 | |
CN114258393A (zh) | 具有磷脂酰肌醇3-激酶δ和γ的双重抑制剂活性的杂环化合物及其医药用途 | |
WO2024002376A1 (fr) | Inhibiteurs de prmt5 et leur utilisation | |
CN113429440B (zh) | 一种螺环化合物的前药、其制备方法及其在医药上的应用 | |
WO2022237890A1 (fr) | Composé à cycle fusionné du type azépine et son utilisation pharmaceutique | |
CN115884776B (zh) | 杂环大环化合物及其医药用途 | |
TWI768465B (zh) | 四氫吲唑衍生物及其製備 | |
CN117229295A (zh) | 含氮大环类化合物及其制备方法和医药用途 | |
WO2022166810A1 (fr) | Dérivé azatricyclique condensé, son procédé de préparation et son utilisation en médecine | |
CN116589454A (zh) | 芳香杂环类化合物及其制备方法和医药用途 | |
CN116262749A (zh) | 一类芳杂环取代的化合物及其制备方法和用途 | |
TW202428279A (zh) | 一種kras g12d抑制劑及其應用 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |