EA031671B1 - Твердые формы 2-(трет-бутиламино)-4-((1r,3r,4r)-3-гидрокси-4-метилциклогексиламино)пиримидин-5-карбоксамида, его композиции и способы его применения - Google Patents

Info

Publication number

EA031671B1

EA031671B1 EA201691544A EA201691544A EA031671B1 EA 031671 B1 EA031671 B1 EA 031671B1 EA 201691544 A EA201691544 A EA 201691544A EA 201691544 A EA201691544 A EA 201691544A EA 031671 B1 EA031671 B1 EA 031671B1

Authority

EA

Eurasian Patent Office

Prior art keywords

compound

formula

solvent

methods

solid

Prior art date

2014-01-30

Links

• Espacenet
• Global Dossier
• Discuss

• 238000000034 method Methods 0.000 title claims abstract description 267
• 239000007787 solid Substances 0.000 title claims abstract description 249
• 239000000203 mixture Substances 0.000 title abstract description 103
• QBBRJRLJWXRSHQ-CKYFFXLPSA-N 2-(tert-butylamino)-4-[[(1r,3r,4r)-3-hydroxy-4-methylcyclohexyl]amino]pyrimidine-5-carboxamide Chemical compound C1[C@@H](O)[C@H](C)CC[C@H]1NC1=NC(NC(C)(C)C)=NC=C1C(N)=O QBBRJRLJWXRSHQ-CKYFFXLPSA-N 0.000 title abstract description 9
• 229940125904 compound 1 Drugs 0.000 claims description 159
• 238000000634 powder X-ray diffraction Methods 0.000 claims description 66
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 52
• 208000035475 disorder Diseases 0.000 claims description 35
• 210000004185 liver Anatomy 0.000 claims description 22
• 101000950695 Homo sapiens Mitogen-activated protein kinase 8 Proteins 0.000 claims description 18
• 101000950669 Homo sapiens Mitogen-activated protein kinase 9 Proteins 0.000 claims description 18
• 102100037808 Mitogen-activated protein kinase 8 Human genes 0.000 claims description 18
• 102100037809 Mitogen-activated protein kinase 9 Human genes 0.000 claims description 18
• 108091000080 Phosphotransferase Proteins 0.000 claims description 18
• 102000020233 phosphotransferase Human genes 0.000 claims description 18
• 230000003176 fibrotic effect Effects 0.000 claims description 13
• 230000037361 pathway Effects 0.000 claims description 12
• 206010025135 lupus erythematosus Diseases 0.000 claims description 11
• 206010052779 Transplant rejections Diseases 0.000 claims description 10
• 230000001684 chronic effect Effects 0.000 claims description 10
• 230000002401 inhibitory effect Effects 0.000 claims description 10
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 8
• 206010039710 Scleroderma Diseases 0.000 claims description 8
• 201000009594 Systemic Scleroderma Diseases 0.000 claims description 8
• 206010042953 Systemic sclerosis Diseases 0.000 claims description 8
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 8
• 206010012601 diabetes mellitus Diseases 0.000 claims description 8
• 208000029523 Interstitial Lung disease Diseases 0.000 claims description 7
• 208000017169 kidney disease Diseases 0.000 claims description 7
• 230000002265 prevention Effects 0.000 claims description 6
• 206010016654 Fibrosis Diseases 0.000 claims description 5
• 210000004072 lung Anatomy 0.000 claims description 3
• 230000004761 fibrosis Effects 0.000 claims 1
• 230000005764 inhibitory process Effects 0.000 claims 1
• -1 processes Substances 0.000 abstract description 82
• 230000008569 process Effects 0.000 abstract description 6
• 238000009472 formulation Methods 0.000 abstract description 2
• 150000001875 compounds Chemical class 0.000 description 290
• 239000002904 solvent Substances 0.000 description 149
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 115
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 112
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 107
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 96
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
• 238000000926 separation method Methods 0.000 description 64
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 62
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 57
• 230000003993 interaction Effects 0.000 description 56
• 238000002360 preparation method Methods 0.000 description 56
• 238000002474 experimental method Methods 0.000 description 55
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 53
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 51
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 48
• AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 47
• 238000001953 recrystallisation Methods 0.000 description 46
• 238000002411 thermogravimetry Methods 0.000 description 46
• 125000000217 alkyl group Chemical group 0.000 description 45
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
• 150000003254 radicals Chemical group 0.000 description 40
• 239000012453 solvate Substances 0.000 description 39
• 238000002441 X-ray diffraction Methods 0.000 description 38
• 238000001938 differential scanning calorimetry curve Methods 0.000 description 38
• 238000001757 thermogravimetry curve Methods 0.000 description 34
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
• 238000006243 chemical reaction Methods 0.000 description 31
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 30
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• 239000003795 chemical substances by application Substances 0.000 description 30
• 150000003840 hydrochlorides Chemical class 0.000 description 30
• 239000012296 anti-solvent Substances 0.000 description 28
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 27
• 238000005481 NMR spectroscopy Methods 0.000 description 27
• 235000019439 ethyl acetate Nutrition 0.000 description 27
• 239000000243 solution Substances 0.000 description 27
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
• 238000004458 analytical method Methods 0.000 description 25
• 239000000725 suspension Substances 0.000 description 25
• 210000004027 cell Anatomy 0.000 description 24
• 125000000714 pyrimidinyl group Chemical group 0.000 description 24
• 238000000113 differential scanning calorimetry Methods 0.000 description 23
• 239000007800 oxidant agent Substances 0.000 description 23
• QVJHLJGPSVCTGC-FSDSQADBSA-N (1r,2r,5r)-5-amino-2-methylcyclohexan-1-ol Chemical compound C[C@@H]1CC[C@@H](N)C[C@H]1O QVJHLJGPSVCTGC-FSDSQADBSA-N 0.000 description 22
• 239000003054 catalyst Substances 0.000 description 22
• 239000013078 crystal Substances 0.000 description 22
• 239000000126 substance Substances 0.000 description 22
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
• 238000010438 heat treatment Methods 0.000 description 21
• 238000004811 liquid chromatography Methods 0.000 description 21
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 20
• 238000001816 cooling Methods 0.000 description 20
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
• 125000003118 aryl group Chemical group 0.000 description 18
• 230000015572 biosynthetic process Effects 0.000 description 18
• 229910052757 nitrogen Inorganic materials 0.000 description 18
• RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 17
• 201000010099 disease Diseases 0.000 description 17
• 125000000623 heterocyclic group Chemical group 0.000 description 17
• 239000003960 organic solvent Substances 0.000 description 17
• 150000001412 amines Chemical class 0.000 description 16
• 239000003638 chemical reducing agent Substances 0.000 description 16
• 125000000753 cycloalkyl group Chemical group 0.000 description 16
• 238000001704 evaporation Methods 0.000 description 16
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 15
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
• 230000008020 evaporation Effects 0.000 description 14
• 239000008194 pharmaceutical composition Substances 0.000 description 14
• 208000016261 weight loss Diseases 0.000 description 14
• 230000004580 weight loss Effects 0.000 description 14
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
• 239000003814 drug Substances 0.000 description 13
• 238000002844 melting Methods 0.000 description 13
• 230000008018 melting Effects 0.000 description 13
• 238000003786 synthesis reaction Methods 0.000 description 13
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
• 229940079593 drug Drugs 0.000 description 12
• 239000000843 powder Substances 0.000 description 12
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
• 239000000047 product Substances 0.000 description 12
• MPQAQJSAYDDROO-UHFFFAOYSA-N bis(4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl)boron Chemical compound CC1C(C2(C)C)CC2CC1[B]C(C1C)CC2C(C)(C)C1C2 MPQAQJSAYDDROO-UHFFFAOYSA-N 0.000 description 11
• 238000004296 chiral HPLC Methods 0.000 description 11
• 238000005259 measurement Methods 0.000 description 11
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 11
• HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 11
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
• 239000002253 acid Substances 0.000 description 10
• 238000010511 deprotection reaction Methods 0.000 description 10
• 239000012071 phase Substances 0.000 description 10
• 239000000902 placebo Substances 0.000 description 10
• 229940068196 placebo Drugs 0.000 description 10
• 238000012216 screening Methods 0.000 description 10
• 239000003826 tablet Substances 0.000 description 10
• 238000012546 transfer Methods 0.000 description 10
• OACCNUGECQQVLB-UHFFFAOYSA-N 2,4-dichloropyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=C(Cl)N=C1Cl OACCNUGECQQVLB-UHFFFAOYSA-N 0.000 description 9
• AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 9
• FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 9
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 9
• 238000003556 assay Methods 0.000 description 9
• 125000004432 carbon atom Chemical group C* 0.000 description 9
• 238000000354 decomposition reaction Methods 0.000 description 9
• 238000001035 drying Methods 0.000 description 9
• 238000011534 incubation Methods 0.000 description 9
• 229920006395 saturated elastomer Polymers 0.000 description 9
• 238000001228 spectrum Methods 0.000 description 9
• 210000002700 urine Anatomy 0.000 description 9
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
• 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 8
• 102000019145 JUN kinase activity proteins Human genes 0.000 description 8
• 102000001253 Protein Kinase Human genes 0.000 description 8
• 239000007900 aqueous suspension Substances 0.000 description 8
• 230000037396 body weight Effects 0.000 description 8
• 239000002775 capsule Substances 0.000 description 8
• 208000019425 cirrhosis of liver Diseases 0.000 description 8
• 238000004807 desolvation Methods 0.000 description 8
• 239000002552 dosage form Substances 0.000 description 8
• 150000004965 peroxy acids Chemical class 0.000 description 8
• 108060006633 protein kinase Proteins 0.000 description 8
• 230000009467 reduction Effects 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
• 231100000240 steatosis hepatitis Toxicity 0.000 description 8
• 208000024891 symptom Diseases 0.000 description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 7
• 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 7
• 239000007995 HEPES buffer Substances 0.000 description 7
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 7
• 229920002472 Starch Polymers 0.000 description 7
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 7
• 239000003085 diluting agent Substances 0.000 description 7
• 238000011067 equilibration Methods 0.000 description 7
• 238000001914 filtration Methods 0.000 description 7
• 239000001963 growth medium Substances 0.000 description 7
• 239000003112 inhibitor Substances 0.000 description 7
• 238000004519 manufacturing process Methods 0.000 description 7
• 238000002156 mixing Methods 0.000 description 7
• 235000019698 starch Nutrition 0.000 description 7
• 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
• YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 7
• XMGQYMWWDOXHJM-SNVBAGLBSA-N (-)-α-limonene Chemical compound CC(=C)[C@H]1CCC(C)=CC1 XMGQYMWWDOXHJM-SNVBAGLBSA-N 0.000 description 6
• BLWZIEOGNLHMEX-UHFFFAOYSA-N 4-(tert-butylamino)-2-[(4-hydroxycyclohexyl)amino]pyrimidine-5-carboxamide Chemical compound C1=C(C(N)=O)C(NC(C)(C)C)=NC(NC2CCC(O)CC2)=N1 BLWZIEOGNLHMEX-UHFFFAOYSA-N 0.000 description 6
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
• 238000005698 Diels-Alder reaction Methods 0.000 description 6
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 6
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
• 238000010521 absorption reaction Methods 0.000 description 6
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 6
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 6
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 6
• 239000000872 buffer Substances 0.000 description 6
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
• 239000011093 chipboard Substances 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 238000011161 development Methods 0.000 description 6
• 230000018109 developmental process Effects 0.000 description 6
• 230000000694 effects Effects 0.000 description 6
• 125000002883 imidazolyl group Chemical group 0.000 description 6
• 238000011068 loading method Methods 0.000 description 6
• 238000004949 mass spectrometry Methods 0.000 description 6
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
• 230000001590 oxidative effect Effects 0.000 description 6
• 238000012552 review Methods 0.000 description 6
• 239000012047 saturated solution Substances 0.000 description 6
• 239000008107 starch Substances 0.000 description 6
• 125000001424 substituent group Chemical group 0.000 description 6
• 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 6
• 238000012360 testing method Methods 0.000 description 6
• 238000006969 Curtius rearrangement reaction Methods 0.000 description 5
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 5
• 229910019142 PO4 Inorganic materials 0.000 description 5
• XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 5
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
• 125000004429 atom Chemical group 0.000 description 5
• 150000001540 azides Chemical class 0.000 description 5
• 230000006378 damage Effects 0.000 description 5
• MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 5
• 208000006454 hepatitis Diseases 0.000 description 5
• 231100000283 hepatitis Toxicity 0.000 description 5
• 125000005842 heteroatom Chemical group 0.000 description 5
• 239000001257 hydrogen Substances 0.000 description 5
• 229910052739 hydrogen Inorganic materials 0.000 description 5
• 230000007062 hydrolysis Effects 0.000 description 5
• 238000006460 hydrolysis reaction Methods 0.000 description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
• 239000000546 pharmaceutical excipient Substances 0.000 description 5
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
• 239000010452 phosphate Substances 0.000 description 5
• 239000004810 polytetrafluoroethylene Substances 0.000 description 5
• 229920001343 polytetrafluoroethylene Polymers 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• 102000004169 proteins and genes Human genes 0.000 description 5
• 108090000623 proteins and genes Proteins 0.000 description 5
• QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 description 5
• 239000011541 reaction mixture Substances 0.000 description 5
• 238000011160 research Methods 0.000 description 5
• 150000003839 salts Chemical class 0.000 description 5
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
• 235000017557 sodium bicarbonate Nutrition 0.000 description 5
• 239000011877 solvent mixture Substances 0.000 description 5
• 238000004611 spectroscopical analysis Methods 0.000 description 5
• 238000003756 stirring Methods 0.000 description 5
• 239000000829 suppository Substances 0.000 description 5
• 238000002076 thermal analysis method Methods 0.000 description 5
• 238000004809 thin layer chromatography Methods 0.000 description 5
• ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 description 4
• ULQHZXRYTWQLSD-ZXFLCMHBSA-N 2-chloro-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]pyrimidine-5-carboxamide Chemical compound ClC1=NC=C(C(=N1)N[C@H]1C[C@H]([C@@H](CC1)C)O)C(=O)N ULQHZXRYTWQLSD-ZXFLCMHBSA-N 0.000 description 4
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
• 102000004190 Enzymes Human genes 0.000 description 4
• 108090000790 Enzymes Proteins 0.000 description 4
• 208000004930 Fatty Liver Diseases 0.000 description 4
• 206010019708 Hepatic steatosis Diseases 0.000 description 4
• 239000002841 Lewis acid Substances 0.000 description 4
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
• RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical group OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 4
• 229920004890 Triton X-100 Polymers 0.000 description 4
• 239000008186 active pharmaceutical agent Substances 0.000 description 4
• 230000032683 aging Effects 0.000 description 4
• 125000003710 aryl alkyl group Chemical group 0.000 description 4
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 4
• 239000011230 binding agent Substances 0.000 description 4
• 210000004369 blood Anatomy 0.000 description 4
• 239000008280 blood Substances 0.000 description 4
• 239000001913 cellulose Substances 0.000 description 4
• 230000008859 change Effects 0.000 description 4
• 239000000460 chlorine Substances 0.000 description 4
• 230000007882 cirrhosis Effects 0.000 description 4
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 4
• 238000004090 dissolution Methods 0.000 description 4
• VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 4
• 208000010706 fatty liver disease Diseases 0.000 description 4
• 125000004415 heterocyclylalkyl group Chemical group 0.000 description 4
• 239000004615 ingredient Substances 0.000 description 4
• 239000000543 intermediate Substances 0.000 description 4
• 150000002576 ketones Chemical class 0.000 description 4
• 150000007517 lewis acids Chemical class 0.000 description 4
• 239000007788 liquid Substances 0.000 description 4
• 239000000314 lubricant Substances 0.000 description 4
• 239000002609 medium Substances 0.000 description 4
• 229920000609 methyl cellulose Polymers 0.000 description 4
• 239000001923 methylcellulose Substances 0.000 description 4
• 235000010981 methylcellulose Nutrition 0.000 description 4
• 125000002950 monocyclic group Chemical group 0.000 description 4
• RPMXALUWKZHYOV-UHFFFAOYSA-N nitroethene Chemical group [O-][N+](=O)C=C RPMXALUWKZHYOV-UHFFFAOYSA-N 0.000 description 4
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 4
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 4
• 125000002971 oxazolyl group Chemical group 0.000 description 4
• 150000002924 oxiranes Chemical class 0.000 description 4
• 230000026731 phosphorylation Effects 0.000 description 4
• 238000006366 phosphorylation reaction Methods 0.000 description 4
• 230000036470 plasma concentration Effects 0.000 description 4
• 229920001223 polyethylene glycol Polymers 0.000 description 4
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
• 239000002244 precipitate Substances 0.000 description 4
• 108090000765 processed proteins & peptides Proteins 0.000 description 4
• 230000005855 radiation Effects 0.000 description 4
• 238000004626 scanning electron microscopy Methods 0.000 description 4
• 238000001179 sorption measurement Methods 0.000 description 4
• 230000007863 steatosis Effects 0.000 description 4
• 210000002784 stomach Anatomy 0.000 description 4
• 238000003860 storage Methods 0.000 description 4
• 239000000758 substrate Substances 0.000 description 4
• 235000000346 sugar Nutrition 0.000 description 4
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
• 210000001519 tissue Anatomy 0.000 description 4
• 125000003944 tolyl group Chemical group 0.000 description 4
• 230000009466 transformation Effects 0.000 description 4
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
• 229960003595 (-)- limonene Drugs 0.000 description 3
• HZYRWNUJAOKLLH-UHFFFAOYSA-N 4-(1-bicyclo[1.1.1]pentanylamino)-2-chloropyrimidine-5-carboxamide Chemical compound C12(CC(C1)C2)NC2=NC(=NC=C2C(=O)N)Cl HZYRWNUJAOKLLH-UHFFFAOYSA-N 0.000 description 3
• JYHKEZAZZGNUAN-UHFFFAOYSA-N 4-(tert-butylamino)-2-chloropyrimidine-5-carboxamide Chemical compound C(C)(C)(C)NC1=NC(=NC=C1C(=O)N)Cl JYHKEZAZZGNUAN-UHFFFAOYSA-N 0.000 description 3
• 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 3
• 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 3
• 208000033222 Biliary cirrhosis primary Diseases 0.000 description 3
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
• JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 3
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
• 238000004566 IR spectroscopy Methods 0.000 description 3
• 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 3
• 102000043136 MAP kinase family Human genes 0.000 description 3
• 108091054455 MAP kinase family Proteins 0.000 description 3
• 229930195725 Mannitol Natural products 0.000 description 3
• 206010028813 Nausea Diseases 0.000 description 3
• 206010028980 Neoplasm Diseases 0.000 description 3
• 239000002202 Polyethylene glycol Substances 0.000 description 3
• 208000012654 Primary biliary cholangitis Diseases 0.000 description 3
• 238000001069 Raman spectroscopy Methods 0.000 description 3
• 229930006000 Sucrose Natural products 0.000 description 3
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
• ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 3
• 208000036142 Viral infection Diseases 0.000 description 3
• 206010047700 Vomiting Diseases 0.000 description 3
• 208000027418 Wounds and injury Diseases 0.000 description 3
• 125000004442 acylamino group Chemical group 0.000 description 3
• 238000007605 air drying Methods 0.000 description 3
• 235000010443 alginic acid Nutrition 0.000 description 3
• 229920000615 alginic acid Polymers 0.000 description 3
• 150000004703 alkoxides Chemical class 0.000 description 3
• 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
• 125000003545 alkoxy group Chemical group 0.000 description 3
• 125000005262 alkoxyamine group Chemical group 0.000 description 3
• 125000005605 benzo group Chemical group 0.000 description 3
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
• 229910052794 bromium Inorganic materials 0.000 description 3
• 239000001506 calcium phosphate Substances 0.000 description 3
• 235000011010 calcium phosphates Nutrition 0.000 description 3
• 229910052799 carbon Inorganic materials 0.000 description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
• 235000010980 cellulose Nutrition 0.000 description 3
• 229920002678 cellulose Polymers 0.000 description 3
• 229910052801 chlorine Inorganic materials 0.000 description 3
• 239000000306 component Substances 0.000 description 3
• XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 3
• 238000010586 diagram Methods 0.000 description 3
• 150000002148 esters Chemical class 0.000 description 3
• 238000011049 filling Methods 0.000 description 3
• 239000000796 flavoring agent Substances 0.000 description 3
• 239000011737 fluorine Substances 0.000 description 3
• 229910052731 fluorine Inorganic materials 0.000 description 3
• 235000013355 food flavoring agent Nutrition 0.000 description 3
• 230000009477 glass transition Effects 0.000 description 3
• 229910052736 halogen Inorganic materials 0.000 description 3
• 150000002367 halogens Chemical class 0.000 description 3
• 125000001072 heteroaryl group Chemical group 0.000 description 3
• 238000004128 high performance liquid chromatography Methods 0.000 description 3
• 150000002431 hydrogen Chemical class 0.000 description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
• 208000014674 injury Diseases 0.000 description 3
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
• 125000000842 isoxazolyl group Chemical group 0.000 description 3
• 238000000021 kinase assay Methods 0.000 description 3
• 238000009533 lab test Methods 0.000 description 3
• 239000008101 lactose Substances 0.000 description 3
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
• 239000000594 mannitol Substances 0.000 description 3
• 235000010355 mannitol Nutrition 0.000 description 3
• 239000000463 material Substances 0.000 description 3
• 230000008693 nausea Effects 0.000 description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
• 229910052760 oxygen Inorganic materials 0.000 description 3
• 230000000704 physical effect Effects 0.000 description 3
• 238000001556 precipitation Methods 0.000 description 3
• 229910000029 sodium carbonate Inorganic materials 0.000 description 3
• 235000017550 sodium carbonate Nutrition 0.000 description 3
• 239000011780 sodium chloride Substances 0.000 description 3
• QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
• 238000002336 sorption--desorption measurement Methods 0.000 description 3
• 125000005346 substituted cycloalkyl group Chemical group 0.000 description 3
• 239000005720 sucrose Substances 0.000 description 3
• 239000000454 talc Substances 0.000 description 3
• 229910052623 talc Inorganic materials 0.000 description 3
• 235000012222 talc Nutrition 0.000 description 3
• 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 3
• RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
• 238000002054 transplantation Methods 0.000 description 3
• 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 3
• KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 3
• 238000001195 ultra high performance liquid chromatography Methods 0.000 description 3
• JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 3
• 230000009385 viral infection Effects 0.000 description 3
• 230000008673 vomiting Effects 0.000 description 3
• 239000001993 wax Substances 0.000 description 3
• HKWIETGWMFZMPJ-RYLOHDEPSA-N (1r,2r,5r)-5-amino-2-methylcyclohexan-1-ol;hydrochloride Chemical compound Cl.C[C@@H]1CC[C@@H](N)C[C@H]1O HKWIETGWMFZMPJ-RYLOHDEPSA-N 0.000 description 2
• JONIMGVUGJVFQD-UHFFFAOYSA-N (4-methylphenyl)sulfonylformonitrile Chemical compound CC1=CC=C(S(=O)(=O)C#N)C=C1 JONIMGVUGJVFQD-UHFFFAOYSA-N 0.000 description 2
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
• 238000005160 1H NMR spectroscopy Methods 0.000 description 2
• IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 2
• XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 2
• LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
• 244000215068 Acacia senegal Species 0.000 description 2
• RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
• 241000349731 Afzelia bipindensis Species 0.000 description 2
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
• VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
• 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
• 206010008609 Cholangitis sclerosing Diseases 0.000 description 2
• 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
• 201000004624 Dermatitis Diseases 0.000 description 2
• 229930091371 Fructose Natural products 0.000 description 2
• 239000005715 Fructose Substances 0.000 description 2
• RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
• 108010010803 Gelatin Proteins 0.000 description 2
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
• 229920000084 Gum arabic Polymers 0.000 description 2
• 102000015779 HDL Lipoproteins Human genes 0.000 description 2
• 108010010234 HDL Lipoproteins Proteins 0.000 description 2
• 206010019728 Hepatitis alcoholic Diseases 0.000 description 2
• 241000282412 Homo Species 0.000 description 2
• 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 2
• 108010002350 Interleukin-2 Proteins 0.000 description 2
• ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
• 229930182816 L-glutamine Natural products 0.000 description 2
• 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 2
• GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 2
• 229910010082 LiAlH Inorganic materials 0.000 description 2
• 229910010084 LiAlH4 Inorganic materials 0.000 description 2
• 102100034069 MAP kinase-activated protein kinase 2 Human genes 0.000 description 2
• 108010041955 MAP-kinase-activated kinase 2 Proteins 0.000 description 2
• 241000124008 Mammalia Species 0.000 description 2
• 241001465754 Metazoa Species 0.000 description 2
• 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 2
• 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 2
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
• CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
• CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
• 241000286209 Phasianidae Species 0.000 description 2
• 229920001213 Polysorbate 20 Polymers 0.000 description 2
• 102000001708 Protein Isoforms Human genes 0.000 description 2
• 108010029485 Protein Isoforms Proteins 0.000 description 2
• 201000004681 Psoriasis Diseases 0.000 description 2
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
• DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
• 210000001744 T-lymphocyte Anatomy 0.000 description 2
• 102100023132 Transcription factor Jun Human genes 0.000 description 2
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
• 235000010489 acacia gum Nutrition 0.000 description 2
• 239000000205 acacia gum Substances 0.000 description 2
• 238000010306 acid treatment Methods 0.000 description 2
• 239000004480 active ingredient Substances 0.000 description 2
• 150000001263 acyl chlorides Chemical class 0.000 description 2
• 208000002353 alcoholic hepatitis Diseases 0.000 description 2
• 150000001299 aldehydes Chemical class 0.000 description 2
• 150000001336 alkenes Chemical class 0.000 description 2
• 125000003282 alkyl amino group Chemical group 0.000 description 2
• VXAUWWUXCIMFIM-UHFFFAOYSA-M aluminum;oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Al+3] VXAUWWUXCIMFIM-UHFFFAOYSA-M 0.000 description 2
• 150000001409 amidines Chemical class 0.000 description 2
• 239000012491 analyte Substances 0.000 description 2
• 239000007864 aqueous solution Substances 0.000 description 2
• 239000012131 assay buffer Substances 0.000 description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
• 125000005874 benzothiadiazolyl group Chemical group 0.000 description 2
• 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 2
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
• 210000004556 brain Anatomy 0.000 description 2
• 229910000389 calcium phosphate Inorganic materials 0.000 description 2
• 201000011510 cancer Diseases 0.000 description 2
• 239000004202 carbamide Substances 0.000 description 2
• 239000001768 carboxy methyl cellulose Substances 0.000 description 2
• 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
• 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
• 235000013339 cereals Nutrition 0.000 description 2
• 239000007795 chemical reaction product Substances 0.000 description 2
• 239000007910 chewable tablet Substances 0.000 description 2
• IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
• 235000019868 cocoa butter Nutrition 0.000 description 2
• 229940110456 cocoa butter Drugs 0.000 description 2
• 238000007796 conventional method Methods 0.000 description 2
• OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
• 239000012043 crude product Substances 0.000 description 2
• 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 2
• 125000004093 cyano group Chemical group *C#N 0.000 description 2
• 125000004122 cyclic group Chemical group 0.000 description 2
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([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
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
• 239000012024 dehydrating agents‎ Substances 0.000 description 2
• 230000018044 dehydration Effects 0.000 description 2
• 238000006297 dehydration reaction Methods 0.000 description 2
• 238000002405 diagnostic procedure Methods 0.000 description 2
• 238000010790 dilution Methods 0.000 description 2
• 239000012895 dilution Substances 0.000 description 2
• 239000013024 dilution buffer Substances 0.000 description 2
• SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
• ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
• 238000009826 distribution Methods 0.000 description 2
• 125000005883 dithianyl group Chemical group 0.000 description 2
• 239000003937 drug carrier Substances 0.000 description 2
• 210000005069 ears Anatomy 0.000 description 2
• 238000000921 elemental analysis Methods 0.000 description 2
• 150000002081 enamines Chemical class 0.000 description 2
• 239000002158 endotoxin Substances 0.000 description 2
• 238000006735 epoxidation reaction Methods 0.000 description 2
• 238000011156 evaluation Methods 0.000 description 2
• 239000012091 fetal bovine serum Substances 0.000 description 2
• 238000012921 fluorescence analysis Methods 0.000 description 2
• 210000001035 gastrointestinal tract Anatomy 0.000 description 2
• 239000008273 gelatin Substances 0.000 description 2
• 229920000159 gelatin Polymers 0.000 description 2
• 235000019322 gelatine Nutrition 0.000 description 2
• 235000011852 gelatine desserts Nutrition 0.000 description 2
• 239000011521 glass Substances 0.000 description 2
• 239000008103 glucose Substances 0.000 description 2
• UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
• 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
• 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
• 150000007857 hydrazones Chemical class 0.000 description 2
• 238000006197 hydroboration reaction Methods 0.000 description 2
• ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
• 125000002636 imidazolinyl group Chemical group 0.000 description 2
• 125000005945 imidazopyridyl group Chemical group 0.000 description 2
• 150000003949 imides Chemical class 0.000 description 2
• 150000002466 imines Chemical class 0.000 description 2
• 208000015181 infectious disease Diseases 0.000 description 2
• 230000003834 intracellular effect Effects 0.000 description 2
• 208000002551 irritable bowel syndrome Diseases 0.000 description 2
• 230000000302 ischemic effect Effects 0.000 description 2
• 239000012948 isocyanate Substances 0.000 description 2
• 150000002513 isocyanates Chemical class 0.000 description 2
• 238000002955 isolation Methods 0.000 description 2
• 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
• 150000002540 isothiocyanates Chemical class 0.000 description 2
• 210000003734 kidney Anatomy 0.000 description 2
• GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 2
• 108010052968 leupeptin Proteins 0.000 description 2
• 230000000670 limiting effect Effects 0.000 description 2
• XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
• 229920006008 lipopolysaccharide Polymers 0.000 description 2
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
• 239000012280 lithium aluminium hydride Substances 0.000 description 2
• IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 2
• 208000019423 liver disease Diseases 0.000 description 2
• 239000007937 lozenge Substances 0.000 description 2
• 239000011777 magnesium Substances 0.000 description 2
• 235000019359 magnesium stearate Nutrition 0.000 description 2
• 239000011159 matrix material Substances 0.000 description 2
• 231100000682 maximum tolerated dose Toxicity 0.000 description 2
• 238000002483 medication Methods 0.000 description 2
• LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
• 238000001471 micro-filtration Methods 0.000 description 2
• 238000000386 microscopy Methods 0.000 description 2
• 239000012046 mixed solvent Substances 0.000 description 2
• 230000004048 modification Effects 0.000 description 2
• 238000012986 modification Methods 0.000 description 2
• 125000002757 morpholinyl group Chemical group 0.000 description 2
• 125000001624 naphthyl group Chemical group 0.000 description 2
• 238000010899 nucleation Methods 0.000 description 2
• 238000000399 optical microscopy Methods 0.000 description 2
• 210000000056 organ Anatomy 0.000 description 2
• 239000012044 organic layer Substances 0.000 description 2
• 150000002923 oximes Chemical class 0.000 description 2
• 239000001301 oxygen Substances 0.000 description 2
• 238000012856 packing Methods 0.000 description 2
• 229910052763 palladium Inorganic materials 0.000 description 2
• 210000000496 pancreas Anatomy 0.000 description 2
• 239000002245 particle Substances 0.000 description 2
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
• PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 2
• 239000002953 phosphate buffered saline Substances 0.000 description 2
• UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
• 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
• 125000003367 polycyclic group Chemical group 0.000 description 2
• 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
• 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
• 238000003825 pressing Methods 0.000 description 2
• 201000000742 primary sclerosing cholangitis Diseases 0.000 description 2
• 230000037452 priming Effects 0.000 description 2
• 238000012545 processing Methods 0.000 description 2
• QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
• 238000000746 purification Methods 0.000 description 2
• 125000003226 pyrazolyl group Chemical group 0.000 description 2
• 125000002098 pyridazinyl group Chemical group 0.000 description 2
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
• 125000004076 pyridyl group Chemical group 0.000 description 2
• 125000000168 pyrrolyl group Chemical group 0.000 description 2
• 230000006340 racemization Effects 0.000 description 2
• 230000002285 radioactive effect Effects 0.000 description 2
• 206010039073 rheumatoid arthritis Diseases 0.000 description 2
• 231100000279 safety data Toxicity 0.000 description 2
• 238000001878 scanning electron micrograph Methods 0.000 description 2
• 208000010157 sclerosing cholangitis Diseases 0.000 description 2
• 239000013049 sediment Substances 0.000 description 2
• 238000004467 single crystal X-ray diffraction Methods 0.000 description 2
• 210000003491 skin Anatomy 0.000 description 2
• 238000010583 slow cooling Methods 0.000 description 2
• 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
• WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 2
• 239000007858 starting material Substances 0.000 description 2
• 239000011550 stock solution Substances 0.000 description 2
• 239000012089 stop solution Substances 0.000 description 2
• UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
• 238000000967 suction filtration Methods 0.000 description 2
• 150000008163 sugars Chemical class 0.000 description 2
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
• 229940124530 sulfonamide Drugs 0.000 description 2
• 150000003456 sulfonamides Chemical class 0.000 description 2
• 150000003457 sulfones Chemical class 0.000 description 2
• 229910052717 sulfur Inorganic materials 0.000 description 2
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical group ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
• 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
• 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 2
• 125000003831 tetrazolyl group Chemical group 0.000 description 2
• 125000001984 thiazolidinyl group Chemical group 0.000 description 2
• 150000003568 thioethers Chemical class 0.000 description 2
• 150000003573 thiols Chemical class 0.000 description 2
• 238000007070 tosylation reaction Methods 0.000 description 2
• 231100000419 toxicity Toxicity 0.000 description 2
• 230000001988 toxicity Effects 0.000 description 2
• 125000001425 triazolyl group Chemical group 0.000 description 2
• YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
• 238000002562 urinalysis Methods 0.000 description 2
• 239000011592 zinc chloride Substances 0.000 description 2
• 235000005074 zinc chloride Nutrition 0.000 description 2
• JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
• GRWFGVWFFZKLTI-UHFFFAOYSA-N α-pinene Chemical compound CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 description 2
• NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
• 229930006720 (-)-alpha-pinene Natural products 0.000 description 1
• NIQIPYGXPZUDDP-RITPCOANSA-N (1s,3r)-3-aminocyclohexan-1-ol Chemical compound N[C@@H]1CCC[C@H](O)C1 NIQIPYGXPZUDDP-RITPCOANSA-N 0.000 description 1
• NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
• MWEXRLZUDANQDZ-RPENNLSWSA-N (2s)-3-hydroxy-n-[11-[4-[4-[4-[11-[[2-[4-[(2r)-2-hydroxypropyl]triazol-1-yl]acetyl]amino]undecanoyl]piperazin-1-yl]-6-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethylamino]-1,3,5-triazin-2-yl]piperazin-1-yl]-11-oxoundecyl]-2-[4-(3-methylsulfanylpropyl)triazol-1-y Chemical compound N1=NC(CCCSC)=CN1[C@@H](CO)C(=O)NCCCCCCCCCCC(=O)N1CCN(C=2N=C(N=C(NCCOCCOCCOCC#C)N=2)N2CCN(CC2)C(=O)CCCCCCCCCCNC(=O)CN2N=NC(C[C@@H](C)O)=C2)CC1 MWEXRLZUDANQDZ-RPENNLSWSA-N 0.000 description 1
• JRZGPXSSNPTNMA-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C1=CC=C2C(N)CCCC2=C1 JRZGPXSSNPTNMA-UHFFFAOYSA-N 0.000 description 1
• LCGFVWKNXLRFIF-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1=CC=C2CC(N)CCC2=C1 LCGFVWKNXLRFIF-UHFFFAOYSA-N 0.000 description 1
• 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
• MPBKAOHKPAKJDA-VCHYOVAHSA-N 2-(3-aminopropyl)-1-[(e)-(2,2-difluoro-1-phenylethylidene)amino]guanidine Chemical compound NCCCN=C(N)N\N=C(\C(F)F)C1=CC=CC=C1 MPBKAOHKPAKJDA-VCHYOVAHSA-N 0.000 description 1
• JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
• LQKLVOWNBKJRJE-UHFFFAOYSA-N 3-bicyclo[1.1.1]pentanylazanium;chloride Chemical compound Cl.C1C2CC1(N)C2 LQKLVOWNBKJRJE-UHFFFAOYSA-N 0.000 description 1
• RKTQEVMZBCBOSB-UHFFFAOYSA-N 4-aminocyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1CCC(O)CC1 RKTQEVMZBCBOSB-UHFFFAOYSA-N 0.000 description 1
• NPHVLMHNJRXDQF-UHFFFAOYSA-N 4-dibutylphosphanyl-n,n-dimethylaniline Chemical compound CCCCP(CCCC)C1=CC=C(N(C)C)C=C1 NPHVLMHNJRXDQF-UHFFFAOYSA-N 0.000 description 1
• 229930024421 Adenine Natural products 0.000 description 1
• GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
• 229920001817 Agar Polymers 0.000 description 1
• 239000005995 Aluminium silicate Substances 0.000 description 1
• 208000024827 Alzheimer disease Diseases 0.000 description 1
• 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
• 201000001320 Atherosclerosis Diseases 0.000 description 1
• 208000035143 Bacterial infection Diseases 0.000 description 1
• 102000051485 Bcl-2 family Human genes 0.000 description 1
• 108700038897 Bcl-2 family Proteins 0.000 description 1
• 241000283690 Bos taurus Species 0.000 description 1
• QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 1
• JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
• 206010006895 Cachexia Diseases 0.000 description 1
• 241000282472 Canis lupus familiaris Species 0.000 description 1
• 241000283707 Capra Species 0.000 description 1
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
• 241000700198 Cavia Species 0.000 description 1
• 241000282693 Cercopithecidae Species 0.000 description 1
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
• 206010063209 Chronic allograft nephropathy Diseases 0.000 description 1
• 241000207199 Citrus Species 0.000 description 1
• 206010009900 Colitis ulcerative Diseases 0.000 description 1
• 229940126062 Compound A Drugs 0.000 description 1
• 229920002261 Corn starch Polymers 0.000 description 1
• 208000011231 Crohn disease Diseases 0.000 description 1
• 201000001200 Crouzon syndrome-acanthosis nigricans syndrome Diseases 0.000 description 1
• 229910002483 Cu Ka Inorganic materials 0.000 description 1
• 201000003883 Cystic fibrosis Diseases 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
• NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
• 208000006926 Discoid Lupus Erythematosus Diseases 0.000 description 1
• 206010014824 Endotoxic shock Diseases 0.000 description 1
• 241000283086 Equidae Species 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
• 241000282326 Felis catus Species 0.000 description 1
• 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
• 241000287828 Gallus gallus Species 0.000 description 1
• 239000004471 Glycine Substances 0.000 description 1
• 229920002907 Guar gum Polymers 0.000 description 1
• 208000023329 Gun shot wound Diseases 0.000 description 1
• 229940122440 HIV protease inhibitor Drugs 0.000 description 1
• NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
• 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
• 101000628949 Homo sapiens Mitogen-activated protein kinase 10 Proteins 0.000 description 1
• 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
• 208000023105 Huntington disease Diseases 0.000 description 1
• 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
• 102100025087 Insulin receptor substrate 1 Human genes 0.000 description 1
• 101710201824 Insulin receptor substrate 1 Proteins 0.000 description 1
• 102000007330 LDL Lipoproteins Human genes 0.000 description 1
• 108010007622 LDL Lipoproteins Proteins 0.000 description 1
• 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 1
• 206010067125 Liver injury Diseases 0.000 description 1
• 102000002569 MAP Kinase Kinase 4 Human genes 0.000 description 1
• 108010068304 MAP Kinase Kinase 4 Proteins 0.000 description 1
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
• 102100026931 Mitogen-activated protein kinase 10 Human genes 0.000 description 1
• 208000034486 Multi-organ failure Diseases 0.000 description 1
• 208000010718 Multiple Organ Failure Diseases 0.000 description 1
• 241000699670 Mus sp. Species 0.000 description 1
• HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
• 125000000815 N-oxide group Chemical group 0.000 description 1
• 150000001204 N-oxides Chemical class 0.000 description 1
• 229910017912 NH2OH Inorganic materials 0.000 description 1
• 229910020700 Na3VO4 Inorganic materials 0.000 description 1
• 102000007999 Nuclear Proteins Human genes 0.000 description 1
• 108010089610 Nuclear Proteins Proteins 0.000 description 1
• 208000008589 Obesity Diseases 0.000 description 1
• 108700020796 Oncogene Proteins 0.000 description 1
• 241000283973 Oryctolagus cuniculus Species 0.000 description 1
• 206010033645 Pancreatitis Diseases 0.000 description 1
• 208000018737 Parkinson disease Diseases 0.000 description 1
• 241001494479 Pecora Species 0.000 description 1
• 229930182555 Penicillin Natural products 0.000 description 1
• JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
• ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
• 239000004698 Polyethylene Substances 0.000 description 1
• 241000288906 Primates Species 0.000 description 1
• 108010016131 Proto-Oncogene Proteins c-jun Proteins 0.000 description 1
• 102000000427 Proto-Oncogene Proteins c-jun Human genes 0.000 description 1
• WTARULDDTDQWMU-UHFFFAOYSA-N Pseudopinene Natural products C1C2C(C)(C)C1CCC2=C WTARULDDTDQWMU-UHFFFAOYSA-N 0.000 description 1
• 229920001131 Pulp (paper) Polymers 0.000 description 1
• 239000012980 RPMI-1640 medium Substances 0.000 description 1
• 206010063837 Reperfusion injury Diseases 0.000 description 1
• 206010039085 Rhinitis allergic Diseases 0.000 description 1
• 208000034189 Sclerosis Diseases 0.000 description 1
• 206010040070 Septic Shock Diseases 0.000 description 1
• MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
• 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
• DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
• 235000021355 Stearic acid Nutrition 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
• UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
• 108091023040 Transcription factor Proteins 0.000 description 1
• 102000040945 Transcription factor Human genes 0.000 description 1
• 201000006704 Ulcerative Colitis Diseases 0.000 description 1
• 206010052428 Wound Diseases 0.000 description 1
• 238000000441 X-ray spectroscopy Methods 0.000 description 1
• 240000008042 Zea mays Species 0.000 description 1
• 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
• 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
• 230000002159 abnormal effect Effects 0.000 description 1
• 238000009825 accumulation Methods 0.000 description 1
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
• 230000001154 acute effect Effects 0.000 description 1
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
• 239000000654 additive Substances 0.000 description 1
• 229960000643 adenine Drugs 0.000 description 1
• 238000012382 advanced drug delivery Methods 0.000 description 1
• 239000008272 agar Substances 0.000 description 1
• 125000003172 aldehyde group Chemical group 0.000 description 1
• 239000000783 alginic acid Substances 0.000 description 1
• 229960001126 alginic acid Drugs 0.000 description 1
• 150000004781 alginic acids Chemical class 0.000 description 1
• 150000003973 alkyl amines Chemical class 0.000 description 1
• 201000010105 allergic rhinitis Diseases 0.000 description 1
• 229910052782 aluminium Inorganic materials 0.000 description 1
• XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
• 235000012211 aluminium silicate Nutrition 0.000 description 1
• 125000000320 amidine group Chemical group 0.000 description 1
• 125000003277 amino group Chemical group 0.000 description 1
• 230000002491 angiogenic effect Effects 0.000 description 1
• 238000002399 angioplasty Methods 0.000 description 1
• 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
• 235000015197 apple juice Nutrition 0.000 description 1
• 238000013459 approach Methods 0.000 description 1
• 239000008346 aqueous phase Substances 0.000 description 1
• 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
• 125000004104 aryloxy group Chemical group 0.000 description 1
• 208000006673 asthma Diseases 0.000 description 1
• 239000012298 atmosphere Substances 0.000 description 1
• 208000010668 atopic eczema Diseases 0.000 description 1
• 125000005602 azabenzimidazolyl group Chemical group 0.000 description 1
• 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
• 125000002393 azetidinyl group Chemical group 0.000 description 1
• IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
• 125000004069 aziridinyl group Chemical group 0.000 description 1
• 230000001580 bacterial effect Effects 0.000 description 1
• 208000022362 bacterial infectious disease Diseases 0.000 description 1
• HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
• 230000009286 beneficial effect Effects 0.000 description 1
• 230000008901 benefit Effects 0.000 description 1
• 239000000440 bentonite Substances 0.000 description 1
• 229910000278 bentonite Inorganic materials 0.000 description 1
• SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
• 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
• 125000002619 bicyclic group Chemical group 0.000 description 1
• 210000000941 bile Anatomy 0.000 description 1
• 235000010290 biphenyl Nutrition 0.000 description 1
• 239000004305 biphenyl Substances 0.000 description 1
• MPQAQJSAYDDROO-VMAIWCPRSA-N bis[(1r,3r,4s,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]boron Chemical compound C([C@H]([C@@H]1C)[B][C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@H]2C)[C@H]2C(C)(C)[C@@H]1C2 MPQAQJSAYDDROO-VMAIWCPRSA-N 0.000 description 1
• 239000012267 brine Substances 0.000 description 1
• 210000000621 bronchi Anatomy 0.000 description 1
• 206010006451 bronchitis Diseases 0.000 description 1
• 229910000019 calcium carbonate Inorganic materials 0.000 description 1
• 235000010216 calcium carbonate Nutrition 0.000 description 1
• FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
• 239000001354 calcium citrate Substances 0.000 description 1
• QXDMQSPYEZFLGF-UHFFFAOYSA-L calcium oxalate Chemical compound [Ca+2].[O-]C(=O)C([O-])=O QXDMQSPYEZFLGF-UHFFFAOYSA-L 0.000 description 1
• CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
• 235000013539 calcium stearate Nutrition 0.000 description 1
• 239000008116 calcium stearate Substances 0.000 description 1
• OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Inorganic materials [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
• 125000002837 carbocyclic group Chemical group 0.000 description 1
• 229910002091 carbon monoxide Inorganic materials 0.000 description 1
• 230000003197 catalytic effect Effects 0.000 description 1
• 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
• 239000003729 cation exchange resin Substances 0.000 description 1
• 229940023913 cation exchange resins Drugs 0.000 description 1
• 238000000423 cell based assay Methods 0.000 description 1
• 230000036755 cellular response Effects 0.000 description 1
• 238000005119 centrifugation Methods 0.000 description 1
• 210000003679 cervix uteri Anatomy 0.000 description 1
• 238000012512 characterization method Methods 0.000 description 1
• 229920001429 chelating resin Polymers 0.000 description 1
• 238000009614 chemical analysis method Methods 0.000 description 1
• 235000013330 chicken meat Nutrition 0.000 description 1
• 208000003167 cholangitis Diseases 0.000 description 1
• 235000012000 cholesterol Nutrition 0.000 description 1
• 238000004587 chromatography analysis Methods 0.000 description 1
• 208000037976 chronic inflammation Diseases 0.000 description 1
• 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
• 235000020971 citrus fruits Nutrition 0.000 description 1
• 238000005352 clarification Methods 0.000 description 1
• 238000003776 cleavage reaction Methods 0.000 description 1
• 210000001072 colon Anatomy 0.000 description 1
• 239000003086 colorant Substances 0.000 description 1
• 238000012669 compression test Methods 0.000 description 1
• 238000002591 computed tomography Methods 0.000 description 1
• 239000012050 conventional carrier Substances 0.000 description 1
• 235000005822 corn Nutrition 0.000 description 1
• 238000012937 correction Methods 0.000 description 1
• 239000006071 cream Substances 0.000 description 1
• 239000002178 crystalline material Substances 0.000 description 1
• 238000002425 crystallisation Methods 0.000 description 1
• 230000008025 crystallization Effects 0.000 description 1
• 238000002447 crystallographic data Methods 0.000 description 1
• 125000006165 cyclic alkyl group Chemical group 0.000 description 1
• 125000004367 cycloalkylaryl group Chemical group 0.000 description 1
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
• HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 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
• 238000013480 data collection Methods 0.000 description 1
• 238000001514 detection method Methods 0.000 description 1
• 239000000104 diagnostic biomarker Substances 0.000 description 1
• WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
• 238000002050 diffraction method Methods 0.000 description 1
• 125000005433 dihydrobenzodioxinyl group Chemical group O1C(COC2=C1C=CC=C2)* 0.000 description 1
• 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
• 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
• 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
• 125000005594 diketone group Chemical group 0.000 description 1
• 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
• 235000019797 dipotassium phosphate Nutrition 0.000 description 1
• 238000007907 direct compression Methods 0.000 description 1
• 239000002270 dispersing agent Substances 0.000 description 1
• 239000003596 drug target Substances 0.000 description 1
• 238000002003 electron diffraction Methods 0.000 description 1
• 238000000132 electrospray ionisation Methods 0.000 description 1
• 239000000839 emulsion Substances 0.000 description 1
• 125000001240 enamine group Chemical group 0.000 description 1
• 230000002357 endometrial effect Effects 0.000 description 1
• 238000005516 engineering process Methods 0.000 description 1
• 206010015037 epilepsy Diseases 0.000 description 1
• 210000003238 esophagus Anatomy 0.000 description 1
• 125000004185 ester group Chemical group 0.000 description 1
• LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
• UMYZHWLYICNGRQ-UHFFFAOYSA-N ethanol;heptane Chemical compound CCO.CCCCCCC UMYZHWLYICNGRQ-UHFFFAOYSA-N 0.000 description 1
• IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
• MTWSTCXAJXEKJQ-UHFFFAOYSA-N ethyl acetate;2-methoxy-2-methylpropane Chemical compound CCOC(C)=O.COC(C)(C)C MTWSTCXAJXEKJQ-UHFFFAOYSA-N 0.000 description 1
• DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
• 235000019325 ethyl cellulose Nutrition 0.000 description 1
• 229920001249 ethyl cellulose Polymers 0.000 description 1
• 125000006437 ethyl cyclopropyl group Chemical group 0.000 description 1
• 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
• 238000011985 exploratory data analysis Methods 0.000 description 1
• 239000000945 filler Substances 0.000 description 1
• 235000013312 flour Nutrition 0.000 description 1
• 239000006260 foam Substances 0.000 description 1
• 235000013305 food Nutrition 0.000 description 1
• 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
• 230000006870 function Effects 0.000 description 1
• 125000000524 functional group Chemical group 0.000 description 1
• 125000002541 furyl group Chemical group 0.000 description 1
• 238000004817 gas chromatography Methods 0.000 description 1
• 239000000499 gel Substances 0.000 description 1
• 238000001502 gel electrophoresis Methods 0.000 description 1
• 239000007903 gelatin capsule Substances 0.000 description 1
• 235000001727 glucose Nutrition 0.000 description 1
• 239000006481 glucose medium Substances 0.000 description 1
• DHCLVCXQIBBOPH-UHFFFAOYSA-L glycerol 2-phosphate(2-) Chemical compound OCC(CO)OP([O-])([O-])=O DHCLVCXQIBBOPH-UHFFFAOYSA-L 0.000 description 1
• PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
• 229910052737 gold Inorganic materials 0.000 description 1
• 239000010931 gold Substances 0.000 description 1
• 208000024908 graft versus host disease Diseases 0.000 description 1
• 239000008187 granular material Substances 0.000 description 1
• 238000000227 grinding Methods 0.000 description 1
• 235000010417 guar gum Nutrition 0.000 description 1
• 239000000665 guar gum Substances 0.000 description 1
• 229960002154 guar gum Drugs 0.000 description 1
• 210000003128 head Anatomy 0.000 description 1
• 210000002216 heart Anatomy 0.000 description 1
• 231100000234 hepatic damage Toxicity 0.000 description 1
• 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
• 125000005844 heterocyclyloxy group Chemical group 0.000 description 1
• 239000004030 hiv protease inhibitor Substances 0.000 description 1
• 150000004677 hydrates Chemical class 0.000 description 1
• 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
• 125000005597 hydrazone group Chemical group 0.000 description 1
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
• 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
• 238000005984 hydrogenation reaction Methods 0.000 description 1
• 239000001341 hydroxy propyl starch Substances 0.000 description 1
• 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
• 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
• 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
• 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
• 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
• 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
• 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
• GVONPBONFIJAHJ-UHFFFAOYSA-N imidazolidin-4-one Chemical compound O=C1CNCN1 GVONPBONFIJAHJ-UHFFFAOYSA-N 0.000 description 1
• 125000002632 imidazolidinyl group Chemical group 0.000 description 1
• 125000005462 imide group Chemical group 0.000 description 1
• 125000000879 imine group Chemical group 0.000 description 1
• 230000028993 immune response Effects 0.000 description 1
• 230000006872 improvement Effects 0.000 description 1
• 239000012535 impurity Substances 0.000 description 1
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
• 229910052738 indium Inorganic materials 0.000 description 1
• APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
• 125000001041 indolyl group Chemical group 0.000 description 1
• 239000007924 injection Substances 0.000 description 1
• 238000002347 injection Methods 0.000 description 1
• 210000000936 intestine Anatomy 0.000 description 1
• 229910052740 iodine Inorganic materials 0.000 description 1
• 208000028867 ischemia Diseases 0.000 description 1
• IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-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
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
• ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 description 1
• NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
• 125000000468 ketone group Chemical group 0.000 description 1
• 150000002596 lactones Chemical class 0.000 description 1
• 210000000867 larynx Anatomy 0.000 description 1
• 229940087305 limonene Drugs 0.000 description 1
• 235000001510 limonene Nutrition 0.000 description 1
• 239000004973 liquid crystal related substance Substances 0.000 description 1
• 230000008818 liver damage Effects 0.000 description 1
• 238000007449 liver function test Methods 0.000 description 1
• 230000005923 long-lasting effect Effects 0.000 description 1
• 230000007774 longterm Effects 0.000 description 1
• 239000006210 lotion Substances 0.000 description 1
• 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• 229940041616 menthol Drugs 0.000 description 1
• 230000002503 metabolic effect Effects 0.000 description 1
• 239000002207 metabolite Substances 0.000 description 1
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
• 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
• 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
• 229960002216 methylparaben Drugs 0.000 description 1
• 239000003094 microcapsule Substances 0.000 description 1
• 229940016286 microcrystalline cellulose Drugs 0.000 description 1
• 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
• 239000008108 microcrystalline cellulose Substances 0.000 description 1
• 230000000877 morphologic effect Effects 0.000 description 1
• 210000000214 mouth Anatomy 0.000 description 1
• 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
• 201000006417 multiple sclerosis Diseases 0.000 description 1
• 208000010125 myocardial infarction Diseases 0.000 description 1
• 210000003739 neck Anatomy 0.000 description 1
• 201000008383 nephritis Diseases 0.000 description 1
• 150000002825 nitriles Chemical class 0.000 description 1
• 235000020824 obesity Nutrition 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
• 239000002674 ointment Substances 0.000 description 1
• 235000015205 orange juice Nutrition 0.000 description 1
• 201000008482 osteoarthritis Diseases 0.000 description 1
• 210000001672 ovary Anatomy 0.000 description 1
• 230000003647 oxidation Effects 0.000 description 1
• 238000007254 oxidation reaction Methods 0.000 description 1
• 125000003544 oxime group Chemical group 0.000 description 1
• 238000004806 packaging method and process Methods 0.000 description 1
• 229960005489 paracetamol Drugs 0.000 description 1
• 238000007911 parenteral administration Methods 0.000 description 1
• 239000003182 parenteral nutrition solution Substances 0.000 description 1
• 238000003921 particle size analysis Methods 0.000 description 1
• 229940049954 penicillin Drugs 0.000 description 1
• 230000000737 periodic effect Effects 0.000 description 1
• 235000019271 petrolatum Nutrition 0.000 description 1
• 239000008177 pharmaceutical agent Substances 0.000 description 1
• 239000000825 pharmaceutical preparation Substances 0.000 description 1
• 229940127557 pharmaceutical product Drugs 0.000 description 1
• 230000000144 pharmacologic effect Effects 0.000 description 1
• 210000003800 pharynx Anatomy 0.000 description 1
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
• XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
• 239000006187 pill Substances 0.000 description 1
• XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane of uncertain configuration Natural products CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 description 1
• 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
• 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
• 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
• 235000011181 potassium carbonates Nutrition 0.000 description 1
• 229910000160 potassium phosphate Inorganic materials 0.000 description 1
• 235000011009 potassium phosphates Nutrition 0.000 description 1
• 229920001592 potato starch Polymers 0.000 description 1
• 229920003124 powdered cellulose Polymers 0.000 description 1
• 235000019814 powdered cellulose Nutrition 0.000 description 1
• 238000009597 pregnancy test Methods 0.000 description 1
• 238000004321 preservation Methods 0.000 description 1
• 230000002062 proliferating effect Effects 0.000 description 1
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
• 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
• 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
• 229960003415 propylparaben Drugs 0.000 description 1
• 210000002307 prostate Anatomy 0.000 description 1
• 239000003223 protective agent Substances 0.000 description 1
• 239000003909 protein kinase inhibitor Substances 0.000 description 1
• 230000009822 protein phosphorylation Effects 0.000 description 1
• 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
• 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
• 125000003373 pyrazinyl group Chemical group 0.000 description 1
• 150000003217 pyrazoles Chemical class 0.000 description 1
• 125000002755 pyrazolinyl group Chemical group 0.000 description 1
• MISVBCMQSJUHMH-UHFFFAOYSA-N pyrimidine-4,6-diamine Chemical class NC1=CC(N)=NC=N1 MISVBCMQSJUHMH-UHFFFAOYSA-N 0.000 description 1
• 125000001422 pyrrolinyl group Chemical group 0.000 description 1
• 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
• 238000004445 quantitative analysis Methods 0.000 description 1
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
• 239000002994 raw material Substances 0.000 description 1
• 230000035484 reaction time Effects 0.000 description 1
• 230000009257 reactivity Effects 0.000 description 1
• 210000000664 rectum Anatomy 0.000 description 1
• 238000010992 reflux Methods 0.000 description 1
• 230000001105 regulatory effect Effects 0.000 description 1
• 230000001850 reproductive effect Effects 0.000 description 1
• 208000037803 restenosis Diseases 0.000 description 1
• 230000000717 retained effect Effects 0.000 description 1
• 125000006413 ring segment Chemical group 0.000 description 1
• 238000011076 safety test Methods 0.000 description 1
• 238000005185 salting out Methods 0.000 description 1
• 230000007017 scission Effects 0.000 description 1
• 239000000565 sealant Substances 0.000 description 1
• 230000019491 signal transduction Effects 0.000 description 1
• RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
• 235000012239 silicon dioxide Nutrition 0.000 description 1
• 239000002002 slurry Substances 0.000 description 1
• 238000002791 soaking Methods 0.000 description 1
• 239000011734 sodium Substances 0.000 description 1
• 239000001632 sodium acetate Substances 0.000 description 1
• 235000017281 sodium acetate Nutrition 0.000 description 1
• WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
• 235000010234 sodium benzoate Nutrition 0.000 description 1
• 239000004299 sodium benzoate Substances 0.000 description 1
• 229960003885 sodium benzoate Drugs 0.000 description 1
• 229940001607 sodium bisulfite Drugs 0.000 description 1
• 239000012279 sodium borohydride Substances 0.000 description 1
• 229910000033 sodium borohydride Inorganic materials 0.000 description 1
• 229910001467 sodium calcium phosphate Inorganic materials 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
• 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
• 235000010268 sodium methyl p-hydroxybenzoate Nutrition 0.000 description 1
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
• 239000007909 solid dosage form Substances 0.000 description 1
• 239000000600 sorbitol Substances 0.000 description 1
• 235000010356 sorbitol Nutrition 0.000 description 1
• 241000894007 species Species 0.000 description 1
• 210000000952 spleen Anatomy 0.000 description 1
• 239000007921 spray Substances 0.000 description 1
• 239000003381 stabilizer Substances 0.000 description 1
• 238000007619 statistical method Methods 0.000 description 1
• 239000008117 stearic acid Substances 0.000 description 1
• 229960005322 streptomycin Drugs 0.000 description 1
• 125000000565 sulfonamide group Chemical group 0.000 description 1
• 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
• 239000011593 sulfur Substances 0.000 description 1
• 235000011149 sulphuric acid Nutrition 0.000 description 1
• 239000006228 supernatant Substances 0.000 description 1
• 239000013589 supplement Substances 0.000 description 1
• 238000004441 surface measurement Methods 0.000 description 1
• 238000001356 surgical procedure Methods 0.000 description 1
• 239000000375 suspending agent Substances 0.000 description 1
• 239000006188 syrup Substances 0.000 description 1
• 235000020357 syrup Nutrition 0.000 description 1
• 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
• 239000007916 tablet composition Substances 0.000 description 1
• 238000003419 tautomerization reaction Methods 0.000 description 1
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
• 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
• 230000001225 therapeutic effect Effects 0.000 description 1
• 238000001107 thermogravimetry coupled to mass spectrometry Methods 0.000 description 1
• 125000000335 thiazolyl group Chemical group 0.000 description 1
• 125000001544 thienyl group Chemical group 0.000 description 1
• 125000000101 thioether group Chemical group 0.000 description 1
• 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
• LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
• 230000007704 transition Effects 0.000 description 1
• 238000002834 transmittance Methods 0.000 description 1
• 230000008736 traumatic injury Effects 0.000 description 1
• 150000003626 triacylglycerols Chemical class 0.000 description 1
• 125000004306 triazinyl group Chemical group 0.000 description 1
• 235000013337 tricalcium citrate Nutrition 0.000 description 1
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
• 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
• JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
• IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
• 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
• 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
• 210000003932 urinary bladder Anatomy 0.000 description 1
• 210000004291 uterus Anatomy 0.000 description 1
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
• 229920002554 vinyl polymer Polymers 0.000 description 1
• 238000005406 washing Methods 0.000 description 1
• 238000005550 wet granulation Methods 0.000 description 1
• 238000009736 wetting Methods 0.000 description 1
• 239000003871 white petrolatum Substances 0.000 description 1
• 238000003963 x-ray microscopy Methods 0.000 description 1
• 229940075420 xanthine Drugs 0.000 description 1