IL174445A

IL174445A - Substituted isoquinolinone derivatives and pharmaceutical compositions containing the same and uses thereof

Substituted isoquinolinone derivatives and pharmaceutical compositions containing the same and uses thereof

Info

Publication number: IL174445A
Authority: IL; Israel
Prior art keywords: alkyl; fluoro; cycloalkyl; group; compound
Prior art date: 2003-10-03

Application number

IL174445A

Other languages

English (en)

Other versions

IL174445A0 (en

Original Assignee

Portola Pharm Inc

Priority date

2003-10-03

Filing date

2006-03-21

Publication date

2012-02-29

2006-03-21 Application filed by Portola Pharm Inc filed Critical Portola Pharm Inc

2006-08-01 Publication of IL174445A0 publication Critical patent/IL174445A0/en

2012-02-29 Publication of IL174445A publication Critical patent/IL174445A/en

Links

239000008194 pharmaceutical composition Chemical class 0.000 title claims description 26
VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 title description 7
150000001875 compounds Chemical class 0.000 claims description 142
125000000217 alkyl group Chemical group 0.000 claims description 104
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 61
-1 cyano, hydroxy Chemical group 0.000 claims description 58
229910052739 hydrogen Inorganic materials 0.000 claims description 45
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 32
125000001188 haloalkyl group Chemical group 0.000 claims description 29
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
125000003545 alkoxy group Chemical group 0.000 claims description 28
229910052736 halogen Inorganic materials 0.000 claims description 24
229910052799 carbon Inorganic materials 0.000 claims description 21
125000004093 cyano group Chemical group *C#N 0.000 claims description 21
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 19
150000003839 salts Chemical class 0.000 claims description 19
125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 18
125000003282 alkyl amino group Chemical group 0.000 claims description 18
150000002367 halogens Chemical class 0.000 claims description 17
125000000753 cycloalkyl group Chemical group 0.000 claims description 14
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
239000003146 anticoagulant agent Substances 0.000 claims description 12
125000001424 substituent group Chemical group 0.000 claims description 12
125000003342 alkenyl group Chemical group 0.000 claims description 11
125000001589 carboacyl group Chemical group 0.000 claims description 11
125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 11
UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 11
125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 10
208000007536 Thrombosis Diseases 0.000 claims description 10
125000003118 aryl group Chemical group 0.000 claims description 10
239000003795 chemical substances by application Substances 0.000 claims description 10
239000003814 drug Substances 0.000 claims description 10
229910052757 nitrogen Inorganic materials 0.000 claims description 10
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
125000001309 chloro group Chemical group Cl* 0.000 claims description 9
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
125000005843 halogen group Chemical group 0.000 claims description 8
230000000302 ischemic effect Effects 0.000 claims description 7
125000001544 thienyl group Chemical group 0.000 claims description 7
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 5
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
125000000304 alkynyl group Chemical group 0.000 claims description 5
210000004369 blood Anatomy 0.000 claims description 5
239000008280 blood Substances 0.000 claims description 5
229940124597 therapeutic agent Drugs 0.000 claims description 5
125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
206010002388 Angina unstable Diseases 0.000 claims description 4
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 4
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 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
239000005557 antagonist Substances 0.000 claims description 4
230000000702 anti-platelet effect Effects 0.000 claims description 4
201000004332 intermediate coronary syndrome Diseases 0.000 claims description 4
125000004433 nitrogen atom Chemical group N* 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
PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 claims description 4
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 3
206010038563 Reocclusion Diseases 0.000 claims description 3
229960001138 acetylsalicylic acid Drugs 0.000 claims description 3
230000003110 anti-inflammatory effect Effects 0.000 claims description 3
229940127219 anticoagulant drug Drugs 0.000 claims description 3
HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 3
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
125000004438 haloalkoxy group Chemical group 0.000 claims description 3
229960002897 heparin Drugs 0.000 claims description 3
229920000669 heparin Polymers 0.000 claims description 3
239000000546 pharmaceutical excipient Substances 0.000 claims description 3
125000003386 piperidinyl group Chemical group 0.000 claims description 3
125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 2
206010022562 Intermittent claudication Diseases 0.000 claims description 2
206010050496 Reversible ischaemic neurological deficit Diseases 0.000 claims description 2
229940122388 Thrombin inhibitor Drugs 0.000 claims description 2
206010043647 Thrombotic Stroke Diseases 0.000 claims description 2
108090000300 Thromboxane Receptors Proteins 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
229940072645 coumadin Drugs 0.000 claims description 2
239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims description 2
230000003480 fibrinolytic effect Effects 0.000 claims description 2
208000021156 intermittent vascular claudication Diseases 0.000 claims description 2
208000037803 restenosis Diseases 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
125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims 2
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
238000004519 manufacturing process Methods 0.000 claims 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
102000003938 Thromboxane Receptors Human genes 0.000 claims 1
208000010125 myocardial infarction Diseases 0.000 claims 1
239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims 1
229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims 1
239000002570 phosphodiesterase III inhibitor Substances 0.000 claims 1
238000000034 method Methods 0.000 description 193
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 128
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 119
229940100389 Sulfonylurea Drugs 0.000 description 88
YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 87
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 83
239000000203 mixture Substances 0.000 description 61
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 59
230000015572 biosynthetic process Effects 0.000 description 54
235000019439 ethyl acetate Nutrition 0.000 description 51
238000010511 deprotection reaction Methods 0.000 description 49
239000000243 solution Substances 0.000 description 49
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 48
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 46
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
238000005859 coupling reaction Methods 0.000 description 42
210000001772 blood platelet Anatomy 0.000 description 40
230000008878 coupling Effects 0.000 description 40
238000010168 coupling process Methods 0.000 description 40
KTFDYVNEGTXQCV-UHFFFAOYSA-N 2-Thiophenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CS1 KTFDYVNEGTXQCV-UHFFFAOYSA-N 0.000 description 30
238000006243 chemical reaction Methods 0.000 description 30
FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 30
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 27
229940093499 ethyl acetate Drugs 0.000 description 27
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
239000012267 brine Substances 0.000 description 26
239000011541 reaction mixture Substances 0.000 description 26
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
229940124530 sulfonamide Drugs 0.000 description 26
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
239000012044 organic layer Substances 0.000 description 21
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
239000000543 intermediate 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
230000009467 reduction Effects 0.000 description 18
238000004007 reversed phase HPLC Methods 0.000 description 17
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 16
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
239000000377 silicon dioxide Substances 0.000 description 16
238000004440 column chromatography Methods 0.000 description 15
239000000047 product Substances 0.000 description 15
238000005160 1H NMR spectroscopy Methods 0.000 description 14
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
229910052938 sodium sulfate Inorganic materials 0.000 description 14
235000011152 sodium sulphate Nutrition 0.000 description 14
102100037600 P2Y purinoceptor 1 Human genes 0.000 description 13
108010085249 Purinergic P2 Receptors Proteins 0.000 description 13
239000007787 solid Substances 0.000 description 13
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
238000001914 filtration Methods 0.000 description 12
229910052740 iodine Inorganic materials 0.000 description 12
238000011282 treatment Methods 0.000 description 12
230000000694 effects Effects 0.000 description 11
150000001448 anilines Chemical class 0.000 description 10
229910052786 argon Inorganic materials 0.000 description 10
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 10
ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 10
230000027455 binding Effects 0.000 description 9
230000005764 inhibitory process Effects 0.000 description 9
210000004623 platelet-rich plasma Anatomy 0.000 description 9
238000005481 NMR spectroscopy Methods 0.000 description 8
239000002253 acid Substances 0.000 description 8
125000004432 carbon atom Chemical group C* 0.000 description 8
239000012043 crude product Substances 0.000 description 8
230000001419 dependent effect Effects 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
230000002829 reductive effect Effects 0.000 description 8
208000010110 spontaneous platelet aggregation Diseases 0.000 description 8
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 8
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 8
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 7
230000029936 alkylation Effects 0.000 description 7
238000005804 alkylation reaction Methods 0.000 description 7
238000001816 cooling Methods 0.000 description 7
RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
XALLJMFDLUYTTF-UHFFFAOYSA-N ethyl n-(5-chlorothiophen-2-yl)sulfonylcarbamate Chemical compound CCOC(=O)NS(=O)(=O)C1=CC=C(Cl)S1 XALLJMFDLUYTTF-UHFFFAOYSA-N 0.000 description 7
239000000463 material Substances 0.000 description 7
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 7
RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-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
230000002776 aggregation Effects 0.000 description 6
238000004220 aggregation Methods 0.000 description 6
230000002785 anti-thrombosis Effects 0.000 description 6
238000003556 assay Methods 0.000 description 6
ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
239000000872 buffer Substances 0.000 description 6
239000012038 nucleophile Substances 0.000 description 6
229910052763 palladium Inorganic materials 0.000 description 6
238000002360 preparation method Methods 0.000 description 6
230000001732 thrombotic effect Effects 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
241000124008 Mammalia Species 0.000 description 5
239000002168 alkylating agent Substances 0.000 description 5
229940100198 alkylating agent Drugs 0.000 description 5
239000012298 atmosphere Substances 0.000 description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
125000001072 heteroaryl group Chemical group 0.000 description 5
239000012442 inert solvent Substances 0.000 description 5
239000003112 inhibitor Substances 0.000 description 5
229910000027 potassium carbonate Inorganic materials 0.000 description 5
239000002244 precipitate Substances 0.000 description 5
238000000746 purification Methods 0.000 description 5
102000005962 receptors Human genes 0.000 description 5
108020003175 receptors Proteins 0.000 description 5
238000012360 testing method Methods 0.000 description 5
238000010626 work up procedure Methods 0.000 description 5
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 4
SLRNETDLLJMLMR-UHFFFAOYSA-N 4-fluoro-1-nitro-2-propan-2-yloxybenzene Chemical compound CC(C)OC1=CC(F)=CC=C1[N+]([O-])=O SLRNETDLLJMLMR-UHFFFAOYSA-N 0.000 description 4
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
229960000583 acetic acid Drugs 0.000 description 4
230000004913 activation Effects 0.000 description 4
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
239000003054 catalyst Substances 0.000 description 4
239000000706 filtrate Substances 0.000 description 4
238000009472 formulation Methods 0.000 description 4
230000007062 hydrolysis Effects 0.000 description 4
238000006460 hydrolysis reaction Methods 0.000 description 4
125000004356 hydroxy functional group Chemical group O* 0.000 description 4
238000000338 in vitro Methods 0.000 description 4
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
239000010410 layer Substances 0.000 description 4
239000003921 oil Substances 0.000 description 4
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 4
230000002265 prevention Effects 0.000 description 4
229940002612 prodrug Drugs 0.000 description 4
239000000651 prodrug Substances 0.000 description 4
239000000741 silica gel Substances 0.000 description 4
229910002027 silica gel Inorganic materials 0.000 description 4
239000002904 solvent Substances 0.000 description 4
238000001356 surgical procedure Methods 0.000 description 4
LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 4
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
230000001225 therapeutic effect Effects 0.000 description 4
RRQPBSBYXWFWRN-UHFFFAOYSA-N 2-(4-aminophenyl)-6-(cyclopropylamino)-7-fluoroisoquinolin-1-one Chemical compound C1=CC(N)=CC=C1N1C(=O)C2=CC(F)=C(NC3CC3)C=C2C=C1 RRQPBSBYXWFWRN-UHFFFAOYSA-N 0.000 description 3
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FAWMTDSAMOCUAR-UHFFFAOYSA-N 2-bromo-1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(Br)=C1 FAWMTDSAMOCUAR-UHFFFAOYSA-N 0.000 description 3
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