BR112019024509A2 - Glicuronídeo de pró-fármacos dos inibidores da janus quinase - Google Patents

Info

Publication number

BR112019024509A2

BR112019024509A2 BR112019024509-0A BR112019024509A BR112019024509A2 BR 112019024509 A2 BR112019024509 A2 BR 112019024509A2 BR 112019024509 A BR112019024509 A BR 112019024509A BR 112019024509 A2 BR112019024509 A2 BR 112019024509A2

Authority

BR

Brazil

Prior art keywords

methyl

compound

mmol

pct

pyran

Prior art date

2017-05-23

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• 229940122245 Janus kinase inhibitor Drugs 0.000 title abstract description 30
• 150000001875 compounds Chemical class 0.000 abstract description 365
• -1 glucuronide compounds Chemical class 0.000 abstract description 182
• 238000000034 method Methods 0.000 abstract description 73
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 34
• 239000000651 prodrug Substances 0.000 abstract description 22
• 229940002612 prodrug Drugs 0.000 abstract description 22
• 208000018522 Gastrointestinal disease Diseases 0.000 abstract description 17
• 230000002757 inflammatory effect Effects 0.000 abstract description 17
• 229930182480 glucuronide Natural products 0.000 abstract description 15
• 239000000543 intermediate Substances 0.000 abstract description 14
• 239000000243 solution Substances 0.000 description 181
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 154
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 139
• 238000002360 preparation method Methods 0.000 description 120
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 109
• 125000000217 alkyl group Chemical group 0.000 description 101
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
• 229910052739 hydrogen Inorganic materials 0.000 description 91
• 239000001257 hydrogen Substances 0.000 description 91
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
• 150000003839 salts Chemical class 0.000 description 83
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 81
• 230000002829 reductive effect Effects 0.000 description 81
• 238000006243 chemical reaction Methods 0.000 description 74
• 239000011541 reaction mixture Substances 0.000 description 70
• 239000000203 mixture Substances 0.000 description 69
• 125000005843 halogen group Chemical group 0.000 description 68
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 61
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 58
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 55
• 125000001072 heteroaryl group Chemical group 0.000 description 54
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
• 125000003545 alkoxy group Chemical group 0.000 description 52
• 125000003118 aryl group Chemical group 0.000 description 50
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 50
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 49
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
• 239000007787 solid Substances 0.000 description 45
• ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 44
• 125000000623 heterocyclic group Chemical group 0.000 description 42
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 41
• 235000019439 ethyl acetate Nutrition 0.000 description 41
• 238000004440 column chromatography Methods 0.000 description 40
• 239000002253 acid Substances 0.000 description 35
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 34
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 34
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
• 239000013543 active substance Substances 0.000 description 33
• 125000004093 cyano group Chemical group *C#N 0.000 description 32
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 29
• 239000003112 inhibitor Substances 0.000 description 28
• 125000000753 cycloalkyl group Chemical group 0.000 description 27
• 229910052938 sodium sulfate Inorganic materials 0.000 description 27
• 235000011152 sodium sulphate Nutrition 0.000 description 27
• 239000000460 chlorine Substances 0.000 description 26
• 239000003795 chemical substances by application Substances 0.000 description 25
• 125000001153 fluoro group Chemical group F* 0.000 description 25
• 239000002904 solvent Substances 0.000 description 25
• 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 24
• 239000010410 layer Substances 0.000 description 24
• 239000012044 organic layer Substances 0.000 description 24
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 22
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 21
• 229910052760 oxygen Inorganic materials 0.000 description 21
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 20
• 102000008096 B7-H1 Antigen Human genes 0.000 description 20
• 108010074708 B7-H1 Antigen Proteins 0.000 description 20
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 20
• 125000001309 chloro group Chemical group Cl* 0.000 description 20
• MQAYFGXOFCEZRW-UHFFFAOYSA-N oxane-2-carboxylic acid Chemical compound OC(=O)C1CCCCO1 MQAYFGXOFCEZRW-UHFFFAOYSA-N 0.000 description 20
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 20
• NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 20
• 210000001072 colon Anatomy 0.000 description 19
• 238000012544 monitoring process Methods 0.000 description 19
• HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 19
• 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 18
• 229960000215 ruxolitinib Drugs 0.000 description 18
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
• HJWLJNBZVZDLAQ-HAQNSBGRSA-N chembl2103874 Chemical compound C1C[C@@H](CS(=O)(=O)NC)CC[C@@H]1N(C)C1=NC=NC2=C1C=CN2 HJWLJNBZVZDLAQ-HAQNSBGRSA-N 0.000 description 17
• 229910052801 chlorine Inorganic materials 0.000 description 17
• 229960004955 oclacitinib Drugs 0.000 description 17
• 239000003826 tablet Substances 0.000 description 17
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• XUZMWHLSFXCVMG-UHFFFAOYSA-N baricitinib Chemical compound C1N(S(=O)(=O)CC)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 XUZMWHLSFXCVMG-UHFFFAOYSA-N 0.000 description 16
• 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 16
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
• 239000005909 Kieselgur Substances 0.000 description 15
• 229950000971 baricitinib Drugs 0.000 description 15
• 229910052757 nitrogen Inorganic materials 0.000 description 15
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 14
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
• 239000002775 capsule Substances 0.000 description 14
• 150000008134 glucuronides Chemical class 0.000 description 14
• 125000005842 heteroatom Chemical group 0.000 description 14
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
• 238000004809 thin layer chromatography Methods 0.000 description 14
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 13
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 13
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 13
• 239000001301 oxygen Chemical group 0.000 description 13
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 12
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 12
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
• 239000000741 silica gel Substances 0.000 description 12
• 229910002027 silica gel Inorganic materials 0.000 description 12
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
• 229910052717 sulfur Chemical group 0.000 description 12
• 239000011593 sulfur Chemical group 0.000 description 12
• 125000004432 carbon atom Chemical group C* 0.000 description 11
• 239000003814 drug Substances 0.000 description 11
• 239000003937 drug carrier Substances 0.000 description 11
• 238000004128 high performance liquid chromatography Methods 0.000 description 11
• 230000001900 immune effect Effects 0.000 description 11
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 11
• 102000008203 CTLA-4 Antigen Human genes 0.000 description 10
• 108010021064 CTLA-4 Antigen Proteins 0.000 description 10
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
• 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 10
• UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 10
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• 208000010643 digestive system disease Diseases 0.000 description 10
• 239000000706 filtrate Substances 0.000 description 10
• 208000018685 gastrointestinal system disease Diseases 0.000 description 10
• 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 10
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
• 238000000746 purification Methods 0.000 description 10
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 9
• 102000004190 Enzymes Human genes 0.000 description 9
• 108090000790 Enzymes Proteins 0.000 description 9
• 102000015617 Janus Kinases Human genes 0.000 description 9
• 108010024121 Janus Kinases Proteins 0.000 description 9
• 241000124008 Mammalia Species 0.000 description 9
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 125000002252 acyl group Chemical group 0.000 description 9
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• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 8
• FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 8
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
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