KR20060113699A - 치환된 이소퀴놀리논 - Google Patents

Info

Publication number

KR20060113699A

KR20060113699A KR1020067008642A KR20067008642A KR20060113699A KR 20060113699 A KR20060113699 A KR 20060113699A KR 1020067008642 A KR1020067008642 A KR 1020067008642A KR 20067008642 A KR20067008642 A KR 20067008642A KR 20060113699 A KR20060113699 A KR 20060113699A

Authority

KR

South Korea

Prior art keywords

alkyl

cycloalkyl

hydrogen

group

amino

Prior art date

2003-10-03

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

Links

• Espacenet
• Global Dossier
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• VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 title abstract description 10
• 208000007536 Thrombosis Diseases 0.000 claims abstract description 16
• 238000000034 method Methods 0.000 claims description 248
• 125000000217 alkyl group Chemical group 0.000 claims description 157
• 150000001875 compounds Chemical class 0.000 claims description 152
• -1 cyano, hydroxy Chemical group 0.000 claims description 134
• 239000001257 hydrogen Substances 0.000 claims description 107
• 229910052739 hydrogen Inorganic materials 0.000 claims description 107
• 150000002431 hydrogen Chemical class 0.000 claims description 66
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 55
• 125000003545 alkoxy group Chemical group 0.000 claims description 48
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 46
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 40
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 38
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
• 229910052736 halogen Inorganic materials 0.000 claims description 31
• 150000002367 halogens Chemical class 0.000 claims description 31
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 25
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 23
• 125000003342 alkenyl group Chemical group 0.000 claims description 20
• 125000000304 alkynyl group Chemical group 0.000 claims description 20
• 150000003839 salts Chemical class 0.000 claims description 20
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 16
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 16
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 16
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 15
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 15
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
• 125000003282 alkyl amino group Chemical group 0.000 claims description 15
• 125000001188 haloalkyl group Chemical group 0.000 claims description 15
• UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
• 125000004423 acyloxy group Chemical group 0.000 claims description 13
• 239000003146 anticoagulant agent Substances 0.000 claims description 12
• 125000003118 aryl group Chemical group 0.000 claims description 12
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
• 229910052757 nitrogen Inorganic materials 0.000 claims description 10
• 125000001544 thienyl group Chemical group 0.000 claims description 10
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 239000003795 chemical substances by application Substances 0.000 claims description 8
• HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 6
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
• 239000005557 antagonist Substances 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 230000000302 ischemic effect Effects 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 5
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• 206010002388 Angina unstable Diseases 0.000 claims description 4
• 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 4
• 208000007718 Stable Angina Diseases 0.000 claims description 4
• 208000032109 Transient ischaemic attack Diseases 0.000 claims description 4
• 208000007814 Unstable Angina Diseases 0.000 claims description 4
• 125000002252 acyl group Chemical group 0.000 claims description 4
• 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
• 230000000702 anti-platelet effect Effects 0.000 claims description 4
• 229940127219 anticoagulant drug Drugs 0.000 claims description 4
• 210000004369 blood Anatomy 0.000 claims description 4
• 239000008280 blood Substances 0.000 claims description 4
• 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 4
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 208000037803 restenosis Diseases 0.000 claims description 4
• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 4
• 201000010875 transient cerebral ischemia Diseases 0.000 claims description 4
• BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 3
• 229960001138 acetylsalicylic acid Drugs 0.000 claims description 3
• 229960002897 heparin Drugs 0.000 claims description 3
• 229920000669 heparin Polymers 0.000 claims description 3
• 229940118179 lovenox Drugs 0.000 claims description 3
• 206010022562 Intermittent claudication Diseases 0.000 claims description 2
• 229940122388 Thrombin inhibitor Drugs 0.000 claims description 2
• 230000001154 acute effect Effects 0.000 claims description 2
• 239000003529 anticholesteremic agent Substances 0.000 claims description 2
• 229940127226 anticholesterol agent Drugs 0.000 claims description 2
• 238000007887 coronary angioplasty Methods 0.000 claims description 2
• 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims description 2
• 239000003527 fibrinolytic agent Substances 0.000 claims description 2
• 208000021156 intermittent vascular claudication Diseases 0.000 claims description 2
• 208000010125 myocardial infarction Diseases 0.000 claims description 2
• 210000005036 nerve Anatomy 0.000 claims description 2
• 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 2
• 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 2
• 239000002570 phosphodiesterase III inhibitor Substances 0.000 claims description 2
• 230000002441 reversible effect Effects 0.000 claims description 2
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
• 229940076279 serotonin Drugs 0.000 claims description 2
• 239000003868 thrombin inhibitor Substances 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
• 229940124597 therapeutic agent Drugs 0.000 claims 4
• 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims 3
• 206010043647 Thrombotic Stroke Diseases 0.000 claims 1
• 229940123987 Thromboxane A2 receptor antagonist Drugs 0.000 claims 1
• 230000007547 defect Effects 0.000 claims 1
• 239000003937 drug carrier Substances 0.000 claims 1
• 239000003769 thromboxane A2 receptor blocking agent Substances 0.000 claims 1
• 238000011282 treatment Methods 0.000 abstract description 20
• 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
• 230000005764 inhibitory process Effects 0.000 abstract description 7
• 208000035475 disorder Diseases 0.000 abstract description 4
• 201000010099 disease Diseases 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 125
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 120
• 229940100389 Sulfonylurea Drugs 0.000 description 87
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 85
• YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 84
• 239000000460 chlorine Substances 0.000 description 69
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 63
• KTFDYVNEGTXQCV-UHFFFAOYSA-N 2-Thiophenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CS1 KTFDYVNEGTXQCV-UHFFFAOYSA-N 0.000 description 61
• 238000010511 deprotection reaction Methods 0.000 description 61
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 58
• 238000005859 coupling reaction Methods 0.000 description 54
• 230000015572 biosynthetic process Effects 0.000 description 53
• 230000008878 coupling Effects 0.000 description 52
• 238000010168 coupling process Methods 0.000 description 52
• 235000019439 ethyl acetate Nutrition 0.000 description 51
• 239000000203 mixture Substances 0.000 description 50
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
• 239000000243 solution Substances 0.000 description 39
• 210000001772 blood platelet Anatomy 0.000 description 36
• 239000011541 reaction mixture Substances 0.000 description 33
• 238000005160 1H NMR spectroscopy Methods 0.000 description 26
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
• 239000012267 brine Substances 0.000 description 25
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
• 238000006243 chemical reaction Methods 0.000 description 22
• 239000012044 organic layer Substances 0.000 description 22
• 230000009467 reduction Effects 0.000 description 22
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 21
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 20
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
• XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 19
• 239000008196 pharmacological composition Substances 0.000 description 19
• 239000000725 suspension Substances 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• 239000000543 intermediate Substances 0.000 description 18
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
• UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 17
• 238000004007 reversed phase HPLC Methods 0.000 description 17
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
• 239000000377 silicon dioxide Substances 0.000 description 16
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
• 238000004440 column chromatography Methods 0.000 description 15
• 239000000047 product Substances 0.000 description 15
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
• 229910052938 sodium sulfate Inorganic materials 0.000 description 13
• 235000011152 sodium sulphate Nutrition 0.000 description 13
• 239000007787 solid Substances 0.000 description 13
• JHLVEBNWCCKSGY-UHFFFAOYSA-N tert-butyl n-methylcarbamate Chemical compound CNC(=O)OC(C)(C)C JHLVEBNWCCKSGY-UHFFFAOYSA-N 0.000 description 13
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
• 229910052786 argon Inorganic materials 0.000 description 12
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 12
• 229910000024 caesium carbonate Inorganic materials 0.000 description 12
• 125000001424 substituent group Chemical group 0.000 description 12
• 229940124530 sulfonamide Drugs 0.000 description 12
• 102100037600 P2Y purinoceptor 1 Human genes 0.000 description 11
• 108010085249 Purinergic P2 Receptors Proteins 0.000 description 11
• 238000001914 filtration Methods 0.000 description 11
• 239000011734 sodium Substances 0.000 description 11
• 230000027455 binding Effects 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
• PAFCHZQEOGJBRT-UHFFFAOYSA-N tert-butyl n-(7-fluoro-1-oxo-2h-isoquinolin-6-yl)-n-methylcarbamate Chemical compound C1=CNC(=O)C2=C1C=C(N(C(=O)OC(C)(C)C)C)C(F)=C2 PAFCHZQEOGJBRT-UHFFFAOYSA-N 0.000 description 10
• 239000002253 acid Substances 0.000 description 9
• 239000012043 crude product Substances 0.000 description 9
• 150000002148 esters Chemical class 0.000 description 9
• 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 9
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 9
• 210000004623 platelet-rich plasma Anatomy 0.000 description 9
• MNYLLSMVYDGHNO-UHFFFAOYSA-N 7-fluoro-6-methoxy-2h-isoquinolin-1-one Chemical compound C1=CNC(=O)C2=C1C=C(OC)C(F)=C2 MNYLLSMVYDGHNO-UHFFFAOYSA-N 0.000 description 8
• 0 CNc(cc(C=CN(c(cc1)ccc1NC(NS(c1ccc(C(F)F)[s]1)(=O)=O)=*)C1=O)c1c1)c1F Chemical compound CNc(cc(C=CN(c(cc1)ccc1NC(NS(c1ccc(C(F)F)[s]1)(=O)=O)=*)C1=O)c1c1)c1F 0.000 description 8
• 150000001448 anilines Chemical class 0.000 description 8
• 230000000144 pharmacologic effect Effects 0.000 description 8
• CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 7
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
• 238000005804 alkylation reaction Methods 0.000 description 7
• 150000003927 aminopyridines Chemical class 0.000 description 7
• 239000003054 catalyst Substances 0.000 description 7
• 230000001419 dependent effect Effects 0.000 description 7
• 238000000746 purification Methods 0.000 description 7
• DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 7
• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 7
• CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 7
• RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 6
• HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
• OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
• 241000124008 Mammalia Species 0.000 description 6
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
• WLMZTKAZJUWXCB-KQYNXXCUSA-N [(2r,3s,4r,5r)-5-(6-amino-2-methylsulfanylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphono hydrogen phosphate Chemical compound C12=NC(SC)=NC(N)=C2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O WLMZTKAZJUWXCB-KQYNXXCUSA-N 0.000 description 6
• 238000003556 assay Methods 0.000 description 6
• 239000012298 atmosphere Substances 0.000 description 6
• 239000000872 buffer Substances 0.000 description 6
• 238000001816 cooling Methods 0.000 description 6
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
• 239000000463 material Substances 0.000 description 6
• 239000012038 nucleophile Substances 0.000 description 6
• 229910052763 palladium Inorganic materials 0.000 description 6
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
• 238000002360 preparation method Methods 0.000 description 6
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
• HJZIDJBZPYZBCZ-UHFFFAOYSA-N tert-butyl n-[7-fluoro-2-(4-nitrophenyl)-1-oxoisoquinolin-6-yl]carbamate Chemical compound O=C1C=2C=C(F)C(NC(=O)OC(C)(C)C)=CC=2C=CN1C1=CC=C([N+]([O-])=O)C=C1 HJZIDJBZPYZBCZ-UHFFFAOYSA-N 0.000 description 6
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
• RKLQLYBJAZBSEU-UHFFFAOYSA-N 5-chlorothiophene-2-sulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Cl)S1 RKLQLYBJAZBSEU-UHFFFAOYSA-N 0.000 description 5
• QQURWFRNETXFTN-UHFFFAOYSA-N 5-fluoro-2-nitrophenol Chemical compound OC1=CC(F)=CC=C1[N+]([O-])=O QQURWFRNETXFTN-UHFFFAOYSA-N 0.000 description 5
• 229910021595 Copper(I) iodide Inorganic materials 0.000 description 5
• BCZGPPYXVRHXLZ-UHFFFAOYSA-N [7-fluoro-2-(4-nitrophenyl)-1-oxoisoquinolin-6-yl]carbamic acid Chemical compound C1=CC(=CC=C1N2C=CC3=CC(=C(C=C3C2=O)F)NC(=O)O)[N+](=O)[O-] BCZGPPYXVRHXLZ-UHFFFAOYSA-N 0.000 description 5
• 230000002776 aggregation Effects 0.000 description 5
• 238000004220 aggregation Methods 0.000 description 5
• 239000002168 alkylating agent Substances 0.000 description 5
• 229940100198 alkylating agent Drugs 0.000 description 5
• 230000002785 anti-thrombosis Effects 0.000 description 5
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
• 125000001072 heteroaryl group Chemical group 0.000 description 5
• 239000012442 inert solvent Substances 0.000 description 5
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
• 239000002244 precipitate Substances 0.000 description 5
• 229940002612 prodrug Drugs 0.000 description 5
• 239000000651 prodrug Substances 0.000 description 5
• 102000005962 receptors Human genes 0.000 description 5
• 108020003175 receptors Proteins 0.000 description 5
• 230000002829 reductive effect Effects 0.000 description 5
• 238000012360 testing method Methods 0.000 description 5
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