BR112020020078A2 - Composto da fórmula, composição farmacêutica, método de tratamento de câncer e compostos das fórmulas 5 e 13 - Google Patents

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Publication number

BR112020020078A2

BR112020020078A2 BR112020020078-6A BR112020020078A BR112020020078A2 BR 112020020078 A2 BR112020020078 A2 BR 112020020078A2 BR 112020020078 A BR112020020078 A BR 112020020078A BR 112020020078 A2 BR112020020078 A2 BR 112020020078A2

Authority

BR

Brazil

Prior art keywords

mmol

alkyl

methyl

amino

furan

Prior art date

2018-04-08

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 180
• 238000000034 method Methods 0.000 title claims abstract description 37
• 206010028980 Neoplasm Diseases 0.000 title claims abstract description 15
• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
• 238000011282 treatment Methods 0.000 title claims abstract description 15
• 201000011510 cancer Diseases 0.000 title claims abstract description 9
• 150000003839 salts Chemical class 0.000 claims abstract description 29
• -1 3-methylpyrazin-2-yl Chemical group 0.000 claims description 383
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 117
• 125000000623 heterocyclic group Chemical group 0.000 claims description 68
• 125000003118 aryl group Chemical group 0.000 claims description 64
• 125000001072 heteroaryl group Chemical group 0.000 claims description 58
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 56
• 229910052739 hydrogen Inorganic materials 0.000 claims description 36
• 239000001257 hydrogen Substances 0.000 claims description 36
• 125000005842 heteroatom Chemical group 0.000 claims description 34
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 29
• 125000001424 substituent group Chemical group 0.000 claims description 29
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 28
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 20
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 20
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
• 125000002950 monocyclic group Chemical group 0.000 claims description 18
• 229910052736 halogen Inorganic materials 0.000 claims description 17
• 150000002431 hydrogen Chemical class 0.000 claims description 17
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 16
• 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 16
• 125000002619 bicyclic group Chemical group 0.000 claims description 15
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 15
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 14
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
• 150000002367 halogens Chemical group 0.000 claims description 14
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
• 229910052799 carbon Inorganic materials 0.000 claims description 13
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
• 229920006395 saturated elastomer Polymers 0.000 claims description 13
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
• 125000004432 carbon atom Chemical group C* 0.000 claims description 11
• 125000000217 alkyl group Chemical group 0.000 claims description 10
• 125000004043 oxo group Chemical group O=* 0.000 claims description 10
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
• 125000000262 haloalkenyl group Chemical group 0.000 claims description 8
• 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 claims description 7
• 125000001188 haloalkyl group Chemical group 0.000 claims description 7
• 125000000232 haloalkynyl group Chemical group 0.000 claims description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
• 125000004076 pyridyl group Chemical group 0.000 claims description 7
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
• 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 claims description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 5
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
• 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• 125000003277 amino group Chemical group 0.000 claims description 4
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
• 125000001153 fluoro group Chemical group F* 0.000 claims description 4
• 125000002541 furyl group Chemical group 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 125000000335 thiazolyl group Chemical group 0.000 claims description 3
• SSJXIUAHEKJCMH-WDSKDSINSA-N (1s,2s)-cyclohexane-1,2-diamine Chemical compound N[C@H]1CCCC[C@@H]1N SSJXIUAHEKJCMH-WDSKDSINSA-N 0.000 claims description 2
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 2
• 125000006625 (C3-C8) cycloalkyloxy group Chemical group 0.000 claims description 2
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000004429 atom Chemical group 0.000 claims description 2
• 229910052794 bromium Inorganic materials 0.000 claims description 2
• 229910052801 chlorine Inorganic materials 0.000 claims description 2
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 2
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
• 239000002131 composite material Substances 0.000 claims 5
• 239000000203 mixture Substances 0.000 abstract description 307
• 229940127600 A2A receptor antagonist Drugs 0.000 abstract description 4
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 720
• 235000019439 ethyl acetate Nutrition 0.000 description 349
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 338
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 300
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 252
• 238000005481 NMR spectroscopy Methods 0.000 description 182
• 239000011541 reaction mixture Substances 0.000 description 166
• 239000007821 HATU Substances 0.000 description 159
• 239000012267 brine Substances 0.000 description 159
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 158
• 239000000047 product Substances 0.000 description 145
• 239000002253 acid Substances 0.000 description 141
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 132
• 239000000243 solution Substances 0.000 description 130
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 127
• 239000012044 organic layer Substances 0.000 description 127
• 238000012746 preparative thin layer chromatography Methods 0.000 description 118
• 239000007832 Na2SO4 Substances 0.000 description 117
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 117
• 229910052938 sodium sulfate Inorganic materials 0.000 description 117
• 235000011152 sodium sulphate Nutrition 0.000 description 117
• YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 98
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 74
• 239000007787 solid Substances 0.000 description 61
• NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 60
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 59
• 238000004440 column chromatography Methods 0.000 description 57
• YKWJNVFPKLFRRE-UHFFFAOYSA-N chembl276738 Chemical compound N=1N2C(N)=NC=3NN=CC=3C2=NC=1C1=CC=CO1 YKWJNVFPKLFRRE-UHFFFAOYSA-N 0.000 description 51
• 239000011734 sodium Substances 0.000 description 49
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• 239000004698 Polyethylene Substances 0.000 description 45
• 238000006243 chemical reaction Methods 0.000 description 41
• 239000003921 oil Substances 0.000 description 39
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• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 31
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 22
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 20
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
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• OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 15
• 238000002953 preparative HPLC Methods 0.000 description 15
• 239000002904 solvent Substances 0.000 description 15
• 238000012360 testing method Methods 0.000 description 15
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