EA030196B1 - Ингибиторы энхансера zeste гомолога 2 - Google Patents

Info

Publication number

EA030196B1

EA030196B1 EA201592068A EA201592068A EA030196B1 EA 030196 B1 EA030196 B1 EA 030196B1 EA 201592068 A EA201592068 A EA 201592068A EA 201592068 A EA201592068 A EA 201592068A EA 030196 B1 EA030196 B1 EA 030196B1

Authority

EA

Eurasian Patent Office

Prior art keywords

methyl

alkyl

oxo

dihydropyridin

dimethyl

Prior art date

2013-04-30

Links

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• Global Dossier
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• 239000003112 inhibitor Substances 0.000 title abstract description 34
• 102000058017 Enhancer of Zeste Homolog 2 Human genes 0.000 title abstract 3
• 101710196274 Histone-lysine N-methyltransferase EZH2 Proteins 0.000 title abstract 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 223
• -1 (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl Chemical group 0.000 claims description 418
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 139
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 111
• 229910052736 halogen Inorganic materials 0.000 claims description 76
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 74
• 229910052739 hydrogen Inorganic materials 0.000 claims description 74
• 239000001257 hydrogen Substances 0.000 claims description 74
• 125000000217 alkyl group Chemical group 0.000 claims description 64
• 150000003839 salts Chemical class 0.000 claims description 63
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 60
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 54
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 53
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 52
• 150000002367 halogens Chemical class 0.000 claims description 50
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 46
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 45
• DAUYIKBTMNZABP-UHFFFAOYSA-N thiophene-3-carboxamide Chemical compound NC(=O)C=1C=CSC=1 DAUYIKBTMNZABP-UHFFFAOYSA-N 0.000 claims description 33
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 32
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 28
• 229910052757 nitrogen Inorganic materials 0.000 claims description 27
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
• 229910052760 oxygen Inorganic materials 0.000 claims description 21
• 150000002431 hydrogen Chemical class 0.000 claims description 18
• 239000001301 oxygen Substances 0.000 claims description 18
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 18
• 125000003386 piperidinyl group Chemical group 0.000 claims description 17
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 16
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 15
• 125000003545 alkoxy group Chemical group 0.000 claims description 15
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
• 125000004432 carbon atom Chemical group C* 0.000 claims description 15
• 125000005842 heteroatom Chemical group 0.000 claims description 15
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 14
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims description 13
• 229910052717 sulfur Inorganic materials 0.000 claims description 13
• 239000011593 sulfur Substances 0.000 claims description 13
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000002541 furyl group Chemical group 0.000 claims description 11
• 125000001424 substituent group Chemical group 0.000 claims description 11
• 239000000460 chlorine Substances 0.000 claims description 10
• 125000002757 morpholinyl group Chemical group 0.000 claims description 10
• 125000004193 piperazinyl group Chemical group 0.000 claims description 10
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
• 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 claims description 9
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 4
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
• 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 239000011737 fluorine Substances 0.000 claims description 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
• 229910052794 bromium Inorganic materials 0.000 claims description 3
• ISUJAGQKWSTODG-UHFFFAOYSA-N tert-butyl 4-[1-[4-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methylcarbamoyl]-3-methylthiophen-2-yl]propyl]piperidine-1-carboxylate Chemical compound S1C=C(C(=O)NCC=2C(NC(C)=CC=2C)=O)C(C)=C1C(CC)C1CCN(C(=O)OC(C)(C)C)CC1 ISUJAGQKWSTODG-UHFFFAOYSA-N 0.000 claims description 2
• FRTKPKWRJMIGMN-UHFFFAOYSA-N 2-cyano-n-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-4-methylthiophene-3-carboxamide Chemical compound S1C(C#N)=C(C(=O)NCC=2C(NC(C)=CC=2C)=O)C(C)=C1N(CC)C1CCOCC1 FRTKPKWRJMIGMN-UHFFFAOYSA-N 0.000 claims 1
• CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims 1
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
• AHMAQXSPEKRSCD-UHFFFAOYSA-N tert-butyl 3-[3-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methylcarbamoyl]-5-[ethyl(oxan-4-yl)amino]-4-methylthiophen-2-yl]pyrrolidine-1-carboxylate Chemical compound S1C(C2CN(CC2)C(=O)OC(C)(C)C)=C(C(=O)NCC=2C(NC(C)=CC=2C)=O)C(C)=C1N(CC)C1CCOCC1 AHMAQXSPEKRSCD-UHFFFAOYSA-N 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 65
• 206010028980 Neoplasm Diseases 0.000 abstract description 47
• 238000011282 treatment Methods 0.000 abstract description 47
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 25
• 201000011510 cancer Diseases 0.000 abstract description 22
• 238000002360 preparation method Methods 0.000 abstract description 10
• 238000002560 therapeutic procedure Methods 0.000 abstract description 8
• 230000008569 process Effects 0.000 abstract description 2
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 358
• 239000000243 solution Substances 0.000 description 236
• 239000000203 mixture Substances 0.000 description 215
• 239000011541 reaction mixture Substances 0.000 description 191
• 238000005481 NMR spectroscopy Methods 0.000 description 141
• 239000007787 solid Substances 0.000 description 140
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 125
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 117
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 110
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 61
• 235000002639 sodium chloride Nutrition 0.000 description 54
• 239000000741 silica gel Substances 0.000 description 51
• 229910002027 silica gel Inorganic materials 0.000 description 51
• 238000006243 chemical reaction Methods 0.000 description 49
• 125000001072 heteroaryl group Chemical group 0.000 description 49
• 239000000126 substance Substances 0.000 description 45
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 44
• 125000003118 aryl group Chemical group 0.000 description 42
• 239000012044 organic layer Substances 0.000 description 42
• 239000000725 suspension Substances 0.000 description 41
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 41
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 40
• 238000004587 chromatography analysis Methods 0.000 description 37
• 239000012071 phase Substances 0.000 description 37
• 230000000694 effects Effects 0.000 description 35
• 239000003921 oil Substances 0.000 description 35
• 235000019198 oils Nutrition 0.000 description 33
• 239000012267 brine Substances 0.000 description 32
• 239000003795 chemical substances by application Substances 0.000 description 31
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 30
• 229910052700 potassium Inorganic materials 0.000 description 29
• 239000000047 product Substances 0.000 description 29
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 26
• 238000000746 purification Methods 0.000 description 25
• 239000000377 silicon dioxide Substances 0.000 description 24
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 23
• 239000002246 antineoplastic agent Substances 0.000 description 22
• 150000002989 phenols Chemical class 0.000 description 21
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 20
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
• 239000000546 pharmaceutical excipient Substances 0.000 description 19
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 19
• 239000003826 tablet Substances 0.000 description 19
• 108020004414 DNA Proteins 0.000 description 18
• 238000002347 injection Methods 0.000 description 18
• 239000007924 injection Substances 0.000 description 18
• 239000011734 sodium Substances 0.000 description 18
• ZMDPNGUJHPRAMG-UHFFFAOYSA-N 3-(aminomethyl)-4,6-dimethyl-1h-pyridin-2-one;hydrochloride Chemical compound Cl.CC1=CC(C)=C(CN)C(=O)N1 ZMDPNGUJHPRAMG-UHFFFAOYSA-N 0.000 description 17
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 17
• 230000015572 biosynthetic process Effects 0.000 description 17
• 239000000843 powder Substances 0.000 description 17
• 239000012047 saturated solution Substances 0.000 description 17
• 239000007788 liquid Substances 0.000 description 16
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
• 238000004007 reversed phase HPLC Methods 0.000 description 16
• 229920006395 saturated elastomer Polymers 0.000 description 16
• 238000003756 stirring Methods 0.000 description 16
• 238000003786 synthesis reaction Methods 0.000 description 16
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
• 206010065553 Bone marrow failure Diseases 0.000 description 15
• 239000007864 aqueous solution Substances 0.000 description 15
• 239000002552 dosage form Substances 0.000 description 15
• 238000004128 high performance liquid chromatography Methods 0.000 description 15
• 239000000543 intermediate Substances 0.000 description 15
• 239000010410 layer Substances 0.000 description 15
• FCKSGPKSSPUXOP-UHFFFAOYSA-N methyl 4-methylthiophene-3-carboxylate Chemical compound COC(=O)C1=CSC=C1C FCKSGPKSSPUXOP-UHFFFAOYSA-N 0.000 description 15
• 125000002971 oxazolyl group Chemical group 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 14
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
• 239000004480 active ingredient Substances 0.000 description 13
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
• 239000003814 drug Substances 0.000 description 13
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 12
• 125000004399 C1-C4 alkenyl group Chemical group 0.000 description 12
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
• 102100037580 Sesquipedalian-1 Human genes 0.000 description 12
• 101710169844 Sesquipedalian-1 Proteins 0.000 description 12
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
• 239000012299 nitrogen atmosphere Substances 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• 206010006187 Breast cancer Diseases 0.000 description 11
• 206010025323 Lymphomas Diseases 0.000 description 11
• 150000001412 amines Chemical class 0.000 description 11
• 238000004440 column chromatography Methods 0.000 description 11
• 229940127089 cytotoxic agent Drugs 0.000 description 11
• 125000004043 oxo group Chemical group O=* 0.000 description 11
• 239000002904 solvent Substances 0.000 description 11
• WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 11
• 208000026310 Breast neoplasm Diseases 0.000 description 10
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
• 229910052786 argon Inorganic materials 0.000 description 10
• 239000012298 atmosphere Substances 0.000 description 10
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 10
• 229940079593 drug Drugs 0.000 description 10
• 239000012458 free base Substances 0.000 description 10
• 230000002401 inhibitory effect Effects 0.000 description 10
• IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 10
• MBNIQASQLNRJAV-UHFFFAOYSA-N methyl 5-iodo-4-methylthiophene-3-carboxylate Chemical compound COC(=O)C1=CSC(I)=C1C MBNIQASQLNRJAV-UHFFFAOYSA-N 0.000 description 10
• PCJPGNCABBDNJU-UHFFFAOYSA-N 3-(aminomethyl)-4,6-dimethyl-1h-pyridin-2-one Chemical compound CC1=CC(C)=C(CN)C(=O)N1 PCJPGNCABBDNJU-UHFFFAOYSA-N 0.000 description 9
• 108010033040 Histones Proteins 0.000 description 9
• 206010039491 Sarcoma Diseases 0.000 description 9
• 125000004429 atom Chemical group 0.000 description 9
• 239000002775 capsule Substances 0.000 description 9
• 210000003238 esophagus Anatomy 0.000 description 9
• 230000006870 function Effects 0.000 description 9
• 208000005017 glioblastoma Diseases 0.000 description 9
• 239000000314 lubricant Substances 0.000 description 9
• 230000001404 mediated effect Effects 0.000 description 9
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 8
• 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 description 8
• 201000009030 Carcinoma Diseases 0.000 description 8
• AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
• GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 8
• 102000006947 Histones Human genes 0.000 description 8
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 8
• 150000001602 bicycloalkyls Chemical group 0.000 description 8
• 239000011230 binding agent Substances 0.000 description 8
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
• 125000001309 chloro group Chemical group Cl* 0.000 description 8
• 238000000576 coating method Methods 0.000 description 8
• 239000000284 extract Substances 0.000 description 8
• 238000003818 flash chromatography Methods 0.000 description 8
• KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
• CQZPEBDZIWYWEL-UHFFFAOYSA-N methyl 5-amino-4-methylthiophene-3-carboxylate Chemical compound COC(=O)C1=CSC(N)=C1C CQZPEBDZIWYWEL-UHFFFAOYSA-N 0.000 description 8
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
• 108090000623 proteins and genes Proteins 0.000 description 8
• YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 7
• 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 7
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• 238000004458 analytical method Methods 0.000 description 7
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• 150000002148 esters Chemical class 0.000 description 7
• SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 7
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
• 239000012535 impurity Substances 0.000 description 7
• 125000001786 isothiazolyl group Chemical group 0.000 description 7
• 125000000842 isoxazolyl group Chemical group 0.000 description 7
• 201000002364 leukopenia Diseases 0.000 description 7
• 231100001022 leukopenia Toxicity 0.000 description 7
• MQSUJFMBRLFJQD-UHFFFAOYSA-N methyl 5-[1-[4-(dimethylamino)piperidin-1-yl]propyl]-4-methylthiophene-3-carboxylate Chemical compound CCC(N1CCC(CC1)N(C)C)c1scc(C(=O)OC)c1C MQSUJFMBRLFJQD-UHFFFAOYSA-N 0.000 description 7
• 230000019491 signal transduction Effects 0.000 description 7
• 238000010898 silica gel chromatography Methods 0.000 description 7
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 6
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 6
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
• 102000029749 Microtubule Human genes 0.000 description 6
• 108091022875 Microtubule Proteins 0.000 description 6
• 206010033128 Ovarian cancer Diseases 0.000 description 6
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
• 229920002472 Starch Polymers 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 229940122803 Vinca alkaloid Drugs 0.000 description 6
• 239000002585 base Substances 0.000 description 6
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