TWI850492B - 腺苷受體拮抗劑化合物 - Google Patents

Info

Publication number

TWI850492B

TWI850492B TW109140608A TW109140608A TWI850492B TW I850492 B TWI850492 B TW I850492B TW 109140608 A TW109140608 A TW 109140608A TW 109140608 A TW109140608 A TW 109140608A TW I850492 B TWI850492 B TW I850492B

Authority

TW

Taiwan

Prior art keywords

compound

substituted

alkyl

amino

pyrazolo

Prior art date

2019-11-19

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 505
• 229940121359 adenosine receptor antagonist Drugs 0.000 title description 3
• 239000000296 purinergic P1 receptor antagonist Substances 0.000 title description 3
• 238000000034 method Methods 0.000 claims abstract description 75
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• 230000002401 inhibitory effect Effects 0.000 claims abstract description 21
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• 125000000217 alkyl group Chemical group 0.000 claims description 158
• 150000003839 salts Chemical class 0.000 claims description 108
• 229910052736 halogen Inorganic materials 0.000 claims description 105
• 150000002367 halogens Chemical class 0.000 claims description 105
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 63
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 61
• 229910052739 hydrogen Inorganic materials 0.000 claims description 59
• 239000008194 pharmaceutical composition Substances 0.000 claims description 42
• 125000001188 haloalkyl group Chemical group 0.000 claims description 37
• 125000001424 substituent group Chemical group 0.000 claims description 33
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
• 229910052731 fluorine Inorganic materials 0.000 claims description 21
• 125000004076 pyridyl group Chemical group 0.000 claims description 21
• 108010085277 Adenosine A2A receptor Proteins 0.000 claims description 20
• 239000003814 drug Substances 0.000 claims description 14
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• 229910052701 rubidium Inorganic materials 0.000 claims description 9
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• -1 hydrate Substances 0.000 description 142
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• 125000003545 alkoxy group Chemical group 0.000 description 130
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• NJIAKNWTIVDSDA-FQEVSTJZSA-N 7-[4-(1-methylsulfonylpiperidin-4-yl)phenyl]-n-[[(2s)-morpholin-2-yl]methyl]pyrido[3,4-b]pyrazin-5-amine Chemical compound C1CN(S(=O)(=O)C)CCC1C1=CC=C(C=2N=C(NC[C@H]3OCCNC3)C3=NC=CN=C3C=2)C=C1 NJIAKNWTIVDSDA-FQEVSTJZSA-N 0.000 description 85
• 239000000460 chlorine Substances 0.000 description 75
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 73
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 64
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• PCBOWMZAEDDKNH-HOTGVXAUSA-N [4-(trifluoromethoxy)phenyl]methyl (3as,6as)-2-(3-fluoro-4-sulfamoylbenzoyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound C1=C(F)C(S(=O)(=O)N)=CC=C1C(=O)N1C[C@H]2CN(C(=O)OCC=3C=CC(OC(F)(F)F)=CC=3)C[C@@H]2C1 PCBOWMZAEDDKNH-HOTGVXAUSA-N 0.000 description 51
• 238000002953 preparative HPLC Methods 0.000 description 51
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• 229940002612 prodrug Drugs 0.000 description 45
• 239000000651 prodrug Substances 0.000 description 45
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• 229910052757 nitrogen Inorganic materials 0.000 description 42
• 125000004093 cyano group Chemical group *C#N 0.000 description 40
• 125000004432 carbon atom Chemical group C* 0.000 description 35
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• AMCJXWMORREWLX-UHFFFAOYSA-N NC1=NC(=C2C(=N1)N(N=C2)CC1=C(C=C(C=C1F)N)F)C1=CC=CC(=N1)C#N Chemical compound NC1=NC(=C2C(=N1)N(N=C2)CC1=C(C=C(C=C1F)N)F)C1=CC=CC(=N1)C#N AMCJXWMORREWLX-UHFFFAOYSA-N 0.000 description 34
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 34
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 33
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 30
• 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 30
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 29
• 125000003118 aryl group Chemical group 0.000 description 28
• 238000004587 chromatography analysis Methods 0.000 description 27
• 239000003208 petroleum Substances 0.000 description 27
• 210000004027 cell Anatomy 0.000 description 26
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 25
• 201000010099 disease Diseases 0.000 description 25
• 239000012299 nitrogen atmosphere Substances 0.000 description 25
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
• 125000004122 cyclic group Chemical group 0.000 description 21
• 239000002904 solvent Substances 0.000 description 21
• 150000003573 thiols Chemical class 0.000 description 21
• 125000001072 heteroaryl group Chemical group 0.000 description 19
• 125000004429 atom Chemical group 0.000 description 18
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• 239000002464 receptor antagonist Substances 0.000 description 17
• 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 16
• 125000006730 (C2-C5) alkynyl group Chemical group 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
• GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 16
• 239000002253 acid Substances 0.000 description 15
• 230000000694 effects Effects 0.000 description 15
• 229940124530 sulfonamide Drugs 0.000 description 15
• 150000003456 sulfonamides Chemical class 0.000 description 15
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 14
• 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 14
• 230000015572 biosynthetic process Effects 0.000 description 14
• 125000005842 heteroatom Chemical group 0.000 description 14
• 208000027866 inflammatory disease Diseases 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 13
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 12
• 239000011734 sodium Substances 0.000 description 12
• 238000003786 synthesis reaction Methods 0.000 description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
• 125000003342 alkenyl group Chemical group 0.000 description 11
• 125000002619 bicyclic group Chemical group 0.000 description 11
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
• 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 10
• 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 10
• 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 10
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 10
• 125000003368 amide group Chemical group 0.000 description 10
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 10
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• 125000000753 cycloalkyl group Chemical group 0.000 description 10
• 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 10
• 125000005647 linker group Chemical group 0.000 description 10
• 229910052760 oxygen Inorganic materials 0.000 description 10
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• 235000017281 sodium acetate Nutrition 0.000 description 10
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• 229940124597 therapeutic agent Drugs 0.000 description 9
• 238000005160 1H NMR spectroscopy Methods 0.000 description 8
• IRRRYVWUUCHHSW-UHFFFAOYSA-N ClC1=C2C(=NC(=N1)N)N(N=C2)CC1=C(C=C(C=C1F)[N+](=O)[O-])F Chemical compound ClC1=C2C(=NC(=N1)N)N(N=C2)CC1=C(C=C(C=C1F)[N+](=O)[O-])F IRRRYVWUUCHHSW-UHFFFAOYSA-N 0.000 description 8
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
• 239000013543 active substance Substances 0.000 description 8
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
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• 125000000592 heterocycloalkyl group Chemical group 0.000 description 8
• 229920006395 saturated elastomer Polymers 0.000 description 8
• 239000000126 substance Substances 0.000 description 8
• 229910052717 sulfur Chemical group 0.000 description 8
• ASKOHPBJRRSUSJ-UHFFFAOYSA-N 4-chloro-1h-pyrazolo[3,4-d]pyrimidin-6-amine Chemical compound NC1=NC(Cl)=C2C=NNC2=N1 ASKOHPBJRRSUSJ-UHFFFAOYSA-N 0.000 description 7
• 239000002126 C01EB10 - Adenosine Substances 0.000 description 7
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
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• 125000000304 alkynyl group Chemical group 0.000 description 7
• 150000001408 amides Chemical class 0.000 description 7
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• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 7
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• 208000024891 symptom Diseases 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 6
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