PT1767535E - Síntese de epotilonas, respectivos intermediários, análogos e suas utilizações - Google Patents

Info

Publication number

PT1767535E

PT1767535E PT06026750T PT06026750T PT1767535E PT 1767535 E PT1767535 E PT 1767535E PT 06026750 T PT06026750 T PT 06026750T PT 06026750 T PT06026750 T PT 06026750T PT 1767535 E PT1767535 E PT 1767535E

Authority

PT

Portugal

Prior art keywords

aryl

alkyl

hydrogen

heteroaryl

substituted

Prior art date

2002-08-23

Links

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• Global Dossier
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• 229930013356 epothilone Natural products 0.000 title claims description 71
• 238000003786 synthesis reaction Methods 0.000 title description 55
• 230000015572 biosynthetic process Effects 0.000 title description 54
• HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 title description 28
• 239000000543 intermediate Substances 0.000 title description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 162
• 238000000034 method Methods 0.000 claims abstract description 70
• -1 cyclic acetal Chemical class 0.000 claims description 96
• 239000001257 hydrogen Substances 0.000 claims description 93
• 229910052739 hydrogen Inorganic materials 0.000 claims description 93
• 125000003118 aryl group Chemical group 0.000 claims description 86
• 125000000217 alkyl group Chemical group 0.000 claims description 71
• 125000001931 aliphatic group Chemical group 0.000 claims description 60
• 238000006243 chemical reaction Methods 0.000 claims description 60
• 125000001072 heteroaryl group Chemical group 0.000 claims description 60
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 53
• 239000000460 chlorine Substances 0.000 claims description 52
• 125000004122 cyclic group Chemical group 0.000 claims description 49
• 150000003883 epothilone derivatives Chemical class 0.000 claims description 45
• 125000006239 protecting group Chemical group 0.000 claims description 39
• 229910052731 fluorine Inorganic materials 0.000 claims description 38
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 37
• 125000002015 acyclic group Chemical group 0.000 claims description 36
• 229910052799 carbon Inorganic materials 0.000 claims description 33
• 150000002367 halogens Chemical class 0.000 claims description 27
• 229910052760 oxygen Inorganic materials 0.000 claims description 27
• 229910052736 halogen Inorganic materials 0.000 claims description 26
• 238000002360 preparation method Methods 0.000 claims description 26
• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 24
• 238000006798 ring closing metathesis reaction Methods 0.000 claims description 24
• 125000003342 alkenyl group Chemical group 0.000 claims description 21
• 229920000642 polymer Polymers 0.000 claims description 21
• 229910052717 sulfur Inorganic materials 0.000 claims description 19
• 150000002576 ketones Chemical class 0.000 claims description 16
• 125000000304 alkynyl group Chemical group 0.000 claims description 15
• 239000003550 marker Substances 0.000 claims description 14
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• 230000009467 reduction Effects 0.000 claims description 14
• 229910052794 bromium Inorganic materials 0.000 claims description 13
• 239000003153 chemical reaction reagent Substances 0.000 claims description 13
• 229910052801 chlorine Inorganic materials 0.000 claims description 13
• 125000003545 alkoxy group Chemical group 0.000 claims description 12
• 230000002285 radioactive effect Effects 0.000 claims description 12
• 229910052740 iodine Inorganic materials 0.000 claims description 11
• 150000001720 carbohydrates Chemical class 0.000 claims description 10
• PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 claims description 8
• 125000004104 aryloxy group Chemical group 0.000 claims description 7
• 239000011984 grubbs catalyst Substances 0.000 claims description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
• 238000009833 condensation Methods 0.000 claims description 6
• 230000005494 condensation Effects 0.000 claims description 6
• 230000003647 oxidation Effects 0.000 claims description 6
• 238000007254 oxidation reaction Methods 0.000 claims description 6
• AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
• 150000002431 hydrogen Chemical group 0.000 claims 7
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 4
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
• KPLXXWHGAQYTID-UHFFFAOYSA-N benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]ruthenium;tricyclohexylphosphane Chemical group C1CCCCC1P(C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru]=CC1=CC=CC=C1 KPLXXWHGAQYTID-UHFFFAOYSA-N 0.000 claims 1
• 206010028980 Neoplasm Diseases 0.000 abstract description 135
• 201000011510 cancer Diseases 0.000 abstract description 30
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 21
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 186
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 145
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 128
• 239000000203 mixture Substances 0.000 description 111
• 239000000243 solution Substances 0.000 description 91
• 238000005481 NMR spectroscopy Methods 0.000 description 85
• 238000011282 treatment Methods 0.000 description 78
• 241000282414 Homo sapiens Species 0.000 description 74
• 235000019439 ethyl acetate Nutrition 0.000 description 72
• XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XOZIUKBZLSUILX-GIQCAXHBSA-N 0.000 description 71
• RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 68
• 229930012538 Paclitaxel Natural products 0.000 description 67
• 238000011580 nude mouse model Methods 0.000 description 67
• 229960001592 paclitaxel Drugs 0.000 description 67
• 241000699660 Mus musculus Species 0.000 description 66
• 230000037396 body weight Effects 0.000 description 61
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 59
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 58
• XOZIUKBZLSUILX-UHFFFAOYSA-N desoxyepothilone B Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC1C(C)=CC1=CSC(C)=N1 XOZIUKBZLSUILX-UHFFFAOYSA-N 0.000 description 56
• 239000011734 sodium Substances 0.000 description 54
• 238000001802 infusion Methods 0.000 description 53
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
• 230000001225 therapeutic effect Effects 0.000 description 50
• 210000004027 cell Anatomy 0.000 description 47
• 239000003814 drug Substances 0.000 description 41
• 238000003818 flash chromatography Methods 0.000 description 41
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
• 229940079593 drug Drugs 0.000 description 34
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
• 239000007787 solid Substances 0.000 description 33
• 238000003756 stirring Methods 0.000 description 32
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
• 125000003710 aryl alkyl group Chemical group 0.000 description 30
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 29
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
• 230000000694 effects Effects 0.000 description 27
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 27
• 241000699670 Mus sp. Species 0.000 description 26
• 235000019441 ethanol Nutrition 0.000 description 26
• 230000008034 disappearance Effects 0.000 description 25
• QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 description 25
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
• XAYAKDZVINDZGB-MNIDRVIESA-N (4s,7r,8s,9s,10z,13z,16s)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(e)-1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-1-oxacyclohexadeca-10,13-diene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)\C=C/C\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XAYAKDZVINDZGB-MNIDRVIESA-N 0.000 description 23
• 206010006187 Breast cancer Diseases 0.000 description 23
• 208000026310 Breast neoplasm Diseases 0.000 description 23
• 230000010412 perfusion Effects 0.000 description 23
• 125000001424 substituent group Chemical group 0.000 description 23
• 201000008275 breast carcinoma Diseases 0.000 description 22
• HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 22
• 125000004446 heteroarylalkyl group Chemical group 0.000 description 22
• 239000003921 oil Substances 0.000 description 22
• 235000019198 oils Nutrition 0.000 description 22
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
• KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 21
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 21
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 20
• QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 description 20
• 239000011541 reaction mixture Substances 0.000 description 20
• 241001465754 Metazoa Species 0.000 description 19
• 239000002253 acid Substances 0.000 description 19
• 238000000338 in vitro Methods 0.000 description 19
• 239000000377 silicon dioxide Substances 0.000 description 19
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
• 239000012267 brine Substances 0.000 description 18
• 229910052681 coesite Inorganic materials 0.000 description 18
• 229910052906 cristobalite Inorganic materials 0.000 description 18
• 230000003013 cytotoxicity Effects 0.000 description 18
• 231100000135 cytotoxicity Toxicity 0.000 description 18
• 150000003839 salts Chemical class 0.000 description 18
• 235000012239 silicon dioxide Nutrition 0.000 description 18
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
• 229910052682 stishovite Inorganic materials 0.000 description 18
• 229910052905 tridymite Inorganic materials 0.000 description 18
• 210000004881 tumor cell Anatomy 0.000 description 18
• 230000004614 tumor growth Effects 0.000 description 18
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 17
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
• 239000002246 antineoplastic agent Substances 0.000 description 16
• 239000012230 colorless oil Substances 0.000 description 16
• 238000002474 experimental method Methods 0.000 description 16
• 239000000741 silica gel Substances 0.000 description 16
• 229910002027 silica gel Inorganic materials 0.000 description 16
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• 210000002381 plasma Anatomy 0.000 description 15
• 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 14
• 239000003795 chemical substances by application Substances 0.000 description 14
• 208000003747 lymphoid leukemia Diseases 0.000 description 14
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• 238000001727 in vivo Methods 0.000 description 13
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
• 206010009944 Colon cancer Diseases 0.000 description 12
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
• 210000001744 T-lymphocyte Anatomy 0.000 description 12
• 239000012044 organic layer Substances 0.000 description 12
• 230000036515 potency Effects 0.000 description 12
• 238000012746 preparative thin layer chromatography Methods 0.000 description 12
• 238000000746 purification Methods 0.000 description 12
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
• 206010058467 Lung neoplasm malignant Diseases 0.000 description 11
• JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 11
• 230000001472 cytotoxic effect Effects 0.000 description 11
• 125000004447 heteroarylalkenyl group Chemical group 0.000 description 11
• 239000012071 phase Substances 0.000 description 11
• 229940002612 prodrug Drugs 0.000 description 11
• 239000000651 prodrug Substances 0.000 description 11
• 230000002829 reductive effect Effects 0.000 description 11
• 230000001988 toxicity Effects 0.000 description 11
• 231100000419 toxicity Toxicity 0.000 description 11
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 10
• 125000005015 aryl alkynyl group Chemical group 0.000 description 10
• 125000001153 fluoro group Chemical group F* 0.000 description 10
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 10
• 239000010410 layer Substances 0.000 description 10
• 201000005296 lung carcinoma Diseases 0.000 description 10
• 230000036457 multidrug resistance Effects 0.000 description 10
• 239000000047 product Substances 0.000 description 10
• 229920006395 saturated elastomer Polymers 0.000 description 10
• 238000005160 1H NMR spectroscopy Methods 0.000 description 9
• 241000699666 Mus <mouse, genus> Species 0.000 description 9
• 239000011324 bead Substances 0.000 description 9
• 239000012043 crude product Substances 0.000 description 9
• 229920001223 polyethylene glycol Polymers 0.000 description 9
• 239000000725 suspension Substances 0.000 description 9
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
• 102000029749 Microtubule Human genes 0.000 description 8
• 108091022875 Microtubule Proteins 0.000 description 8
• WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 8
• 150000001299 aldehydes Chemical class 0.000 description 8
• 125000005018 aryl alkenyl group Chemical group 0.000 description 8
• 125000004432 carbon atom Chemical group C* 0.000 description 8
• 238000010511 deprotection reaction Methods 0.000 description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
• 239000011737 fluorine Substances 0.000 description 8
• 125000000623 heterocyclic group Chemical group 0.000 description 8
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
• 210000004688 microtubule Anatomy 0.000 description 8
• 239000000843 powder Substances 0.000 description 8
• 238000010992 reflux Methods 0.000 description 8
• 239000011780 sodium chloride Substances 0.000 description 8
• 231100001274 therapeutic index Toxicity 0.000 description 8
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
• 150000001336 alkenes Chemical group 0.000 description 7
• 231100000433 cytotoxic Toxicity 0.000 description 7
• 238000001035 drying Methods 0.000 description 7
• 239000000284 extract Substances 0.000 description 7
• 239000000706 filtrate Substances 0.000 description 7
• 230000012010 growth Effects 0.000 description 7
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 7
• 230000002401 inhibitory effect Effects 0.000 description 7
• 238000006467 substitution reaction Methods 0.000 description 7
• 238000002560 therapeutic procedure Methods 0.000 description 7
• KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 7
• 229960004982 vinblastine sulfate Drugs 0.000 description 7
• XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 6
• HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
• 241000282412 Homo Species 0.000 description 6
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
• 239000007832 Na2SO4 Substances 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
• 125000002252 acyl group Chemical group 0.000 description 6
• 238000004458 analytical method Methods 0.000 description 6
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• 238000000576 coating method Methods 0.000 description 6
• 125000004093 cyano group Chemical group *C#N 0.000 description 6
• 208000035475 disorder Diseases 0.000 description 6
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• 239000003937 drug carrier Substances 0.000 description 6
• 238000009472 formulation Methods 0.000 description 6
• 239000012634 fragment Substances 0.000 description 6
• 125000005312 heteroarylalkynyl group Chemical group 0.000 description 6
• 238000004896 high resolution mass spectrometry Methods 0.000 description 6
• 230000005764 inhibitory process Effects 0.000 description 6
• 239000007924 injection Substances 0.000 description 6
• 238000002347 injection Methods 0.000 description 6
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
• 235000019341 magnesium sulphate Nutrition 0.000 description 6
• NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 6
• 239000000463 material Substances 0.000 description 6
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• 235000011152 sodium sulphate Nutrition 0.000 description 6
• 230000003595 spectral effect Effects 0.000 description 6
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