ES2623175T3 - Dihidropiridona P1 como inhibidores del factor XIA - Google Patents
Dihidropiridona P1 como inhibidores del factor XIA Download PDFInfo
- Publication number
- ES2623175T3 ES2623175T3 ES13747625.5T ES13747625T ES2623175T3 ES 2623175 T3 ES2623175 T3 ES 2623175T3 ES 13747625 T ES13747625 T ES 13747625T ES 2623175 T3 ES2623175 T3 ES 2623175T3
- Authority
- ES
- Spain
- Prior art keywords
- oxo
- methyl
- chloro
- nonadeca
- hexaen
- Prior art date
- 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.)
- Active
Links
- 239000003112 inhibitor Substances 0.000 title description 16
- ZPOODPZCZLCUAN-UHFFFAOYSA-N 3,4-dihydro-1h-pyridin-2-one Chemical compound O=C1CCC=CN1 ZPOODPZCZLCUAN-UHFFFAOYSA-N 0.000 title description 2
- -1 amino, substituted amino Chemical group 0.000 claims abstract description 180
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 47
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 36
- 125000003118 aryl group Chemical group 0.000 claims abstract description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 27
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 24
- 150000002367 halogens Chemical class 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 13
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 9
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 8
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 5
- 101100516554 Caenorhabditis elegans nhr-5 gene Proteins 0.000 claims abstract description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 5
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 151
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims description 107
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 38
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 208000035475 disorder Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 230000009424 thromboembolic effect Effects 0.000 claims description 9
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 206010047249 Venous thrombosis Diseases 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 2
- XCUAIINAJCDIPM-XVFCMESISA-N N(4)-hydroxycytidine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=NO)C=C1 XCUAIINAJCDIPM-XVFCMESISA-N 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- DEKJPODSYVPCPW-ZGZXFVETSA-N 4-(aminomethyl)-N-[(12E,15S)-17,19-diazatricyclo[14.2.1.02,7]nonadeca-1(18),2,4,6,12,16-hexaen-15-yl]cyclohexane-1-carboxamide Chemical compound NCC1CCC(CC1)C(=O)N[C@H]1C\C=C\CCCCc2ccccc2-c2cnc1[nH]2 DEKJPODSYVPCPW-ZGZXFVETSA-N 0.000 claims 12
- 238000011321 prophylaxis Methods 0.000 claims 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims 3
- 125000001425 triazolyl group Chemical group 0.000 claims 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 2
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims 1
- 206010002383 Angina Pectoris Diseases 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 206010003658 Atrial Fibrillation Diseases 0.000 claims 1
- 206010008088 Cerebral artery embolism Diseases 0.000 claims 1
- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims 1
- 206010051055 Deep vein thrombosis Diseases 0.000 claims 1
- 208000005189 Embolism Diseases 0.000 claims 1
- 206010014513 Embolism arterial Diseases 0.000 claims 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 claims 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims 1
- 206010037379 Pulmonary embolism and thrombosis Diseases 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 claims 1
- 230000000747 cardiac effect Effects 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000002541 furyl group Chemical group 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 239000007943 implant Substances 0.000 claims 1
- 201000010849 intracranial embolism Diseases 0.000 claims 1
- 230000000302 ischemic effect Effects 0.000 claims 1
- 125000000842 isoxazolyl group Chemical group 0.000 claims 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims 1
- 125000002757 morpholinyl group Chemical group 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 230000003836 peripheral circulation Effects 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 125000002098 pyridazinyl group Chemical group 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- 125000000168 pyrrolyl group Chemical group 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 125000001544 thienyl group Chemical group 0.000 claims 1
- 201000005060 thrombophlebitis Diseases 0.000 claims 1
- 230000001052 transient effect Effects 0.000 claims 1
- 125000004306 triazinyl group Chemical group 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 6
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 4
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 abstract description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 abstract description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 abstract description 2
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 211
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 180
- 239000000243 solution Substances 0.000 description 135
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
- 238000005160 1H NMR spectroscopy Methods 0.000 description 126
- 238000006243 chemical reaction Methods 0.000 description 107
- 239000007787 solid Substances 0.000 description 93
- 238000004128 high performance liquid chromatography Methods 0.000 description 88
- 239000011541 reaction mixture Substances 0.000 description 88
- 239000000543 intermediate Substances 0.000 description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 76
- 239000012267 brine Substances 0.000 description 67
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 67
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- 239000000203 mixture Substances 0.000 description 64
- 235000019439 ethyl acetate Nutrition 0.000 description 61
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 60
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 49
- 239000000460 chlorine Substances 0.000 description 46
- 239000012044 organic layer Substances 0.000 description 39
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 38
- 235000019341 magnesium sulphate Nutrition 0.000 description 38
- 239000000047 product Substances 0.000 description 38
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 238000000746 purification Methods 0.000 description 33
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- 239000010410 layer Substances 0.000 description 32
- 229910052938 sodium sulfate Inorganic materials 0.000 description 32
- 235000011152 sodium sulphate Nutrition 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 239000012071 phase Substances 0.000 description 25
- 238000010898 silica gel chromatography Methods 0.000 description 25
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 239000003921 oil Substances 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
- 238000002953 preparative HPLC Methods 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- 238000004007 reversed phase HPLC Methods 0.000 description 16
- 108010074864 Factor XI Proteins 0.000 description 15
- 239000007832 Na2SO4 Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 14
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 108010080805 Factor XIa Proteins 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 10
- 239000003146 anticoagulant agent Substances 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 239000000758 substrate Substances 0.000 description 9
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 9
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 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 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 108090000190 Thrombin Proteins 0.000 description 8
- 229910052796 boron Inorganic materials 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229960004072 thrombin Drugs 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 229920000669 heparin Polymers 0.000 description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- HFKZZEDGXXYRDW-UHFFFAOYSA-N 3-chloro-2,6-difluorobenzaldehyde Chemical compound FC1=CC=C(Cl)C(F)=C1C=O HFKZZEDGXXYRDW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 229910002666 PdCl2 Inorganic materials 0.000 description 6
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 229940127219 anticoagulant drug Drugs 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000003055 low molecular weight heparin Substances 0.000 description 6
- 229940127215 low-molecular weight heparin Drugs 0.000 description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 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
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Substances CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 125000005620 boronic acid group Chemical class 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 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 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- WDTUCEMLUHTMCB-UHFFFAOYSA-N 5-chloro-2-fluorobenzaldehyde Chemical compound FC1=CC=C(Cl)C=C1C=O WDTUCEMLUHTMCB-UHFFFAOYSA-N 0.000 description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- 208000032843 Hemorrhage Diseases 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229940121765 Protease-activated receptor antagonist Drugs 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 235000011009 potassium phosphates Nutrition 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 238000002604 ultrasonography Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- GQWNPIKWYPQUPI-UHFFFAOYSA-N 2-methylbut-3-enoic acid Chemical compound C=CC(C)C(O)=O GQWNPIKWYPQUPI-UHFFFAOYSA-N 0.000 description 3
- CDQBWRDNICENAT-UHFFFAOYSA-N 5-chloro-2-(1,2,4-triazol-1-yl)benzaldehyde Chemical compound O=CC1=CC(Cl)=CC=C1N1N=CN=C1 CDQBWRDNICENAT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- 102100022641 Coagulation factor IX Human genes 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 108010048049 Factor IXa Proteins 0.000 description 3
- 108010054265 Factor VIIa Proteins 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 108010001014 Plasminogen Activators Proteins 0.000 description 3
- 102000001938 Plasminogen Activators Human genes 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 229940122388 Thrombin inhibitor Drugs 0.000 description 3
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 3
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 206010000891 acute myocardial infarction Diseases 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 230000002785 anti-thrombosis Effects 0.000 description 3
- 239000003416 antiarrhythmic agent Substances 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 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 3
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical compound C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 229940012414 factor viia Drugs 0.000 description 3
- 230000003480 fibrinolytic effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 229940127126 plasminogen activator Drugs 0.000 description 3
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 239000003868 thrombin inhibitor Substances 0.000 description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- GQWNPIKWYPQUPI-SCSAIBSYSA-N (2r)-2-methylbut-3-enoic acid Chemical compound C=C[C@@H](C)C(O)=O GQWNPIKWYPQUPI-SCSAIBSYSA-N 0.000 description 2
- FJWQIPROKHFYJR-LLVKDONJSA-N (3r)-3-[tert-butyl(dimethyl)silyl]oxy-3-(4-chloro-3-fluoropyridin-2-yl)propanal Chemical compound CC(C)(C)[Si](C)(C)O[C@H](CC=O)C1=NC=CC(Cl)=C1F FJWQIPROKHFYJR-LLVKDONJSA-N 0.000 description 2
- 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 description 2
- AQXHUOAITUAMMR-UHFFFAOYSA-N 1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-ol Chemical compound C=CC(O)C1=C(F)C=CC(Cl)=C1F AQXHUOAITUAMMR-UHFFFAOYSA-N 0.000 description 2
- SITPBAQXONVNFO-UHFFFAOYSA-N 1-(3-chloro-2-fluoro-6-methoxyphenyl)prop-2-en-1-one Chemical compound COC1=CC=C(Cl)C(F)=C1C(=O)C=C SITPBAQXONVNFO-UHFFFAOYSA-N 0.000 description 2
- KMZCTRHERHVLAI-UHFFFAOYSA-N 1-(6-bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one Chemical compound FC1=C(Cl)C=CC(Br)=C1C(=O)C=C KMZCTRHERHVLAI-UHFFFAOYSA-N 0.000 description 2
- DVQMPWOLBFKUMM-UHFFFAOYSA-N 2-diethoxyphosphorylacetic acid Chemical compound CCOP(=O)(CC(O)=O)OCC DVQMPWOLBFKUMM-UHFFFAOYSA-N 0.000 description 2
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical compound COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 description 2
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 2
- AUUIARVPJHGTSA-UHFFFAOYSA-N 3-(aminomethyl)chromen-2-one Chemical compound C1=CC=C2OC(=O)C(CN)=CC2=C1 AUUIARVPJHGTSA-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 2
- NZLNQSUMFSPISS-UHFFFAOYSA-N 4-chloropyridine-2-carbaldehyde Chemical compound ClC1=CC=NC(C=O)=C1 NZLNQSUMFSPISS-UHFFFAOYSA-N 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 2
- 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 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 235000008553 Allium fistulosum Nutrition 0.000 description 2
- 244000257727 Allium fistulosum Species 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 2
- 229910015845 BBr3 Inorganic materials 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 2
- 108010076282 Factor IX Proteins 0.000 description 2
- 229940123849 Factor IXa inhibitor Drugs 0.000 description 2
- 229940082863 Factor VIIa inhibitor Drugs 0.000 description 2
- 108010071241 Factor XIIa Proteins 0.000 description 2
- 108010074860 Factor Xa Proteins 0.000 description 2
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 108010007267 Hirudins Proteins 0.000 description 2
- 102000007625 Hirudins Human genes 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- 239000003810 Jones reagent Substances 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 2
- 241000282520 Papio Species 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 108090000113 Plasma Kallikrein Proteins 0.000 description 2
- 102000003827 Plasma Kallikrein Human genes 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 102000002262 Thromboplastin Human genes 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 2
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 2
- 229940024142 alpha 1-antitrypsin Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 2
- 229960003856 argatroban Drugs 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000003130 blood coagulation factor inhibitor Substances 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 229940107161 cholesterol Drugs 0.000 description 2
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 2
- 229960003009 clopidogrel Drugs 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- KQTXIZHBFFWWFW-UHFFFAOYSA-L disilver;carbonate Chemical compound [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960004222 factor ix Drugs 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 238000013100 final test Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 125000004692 haloalkylcarbonyl group Chemical group 0.000 description 2
- 230000023597 hemostasis Effects 0.000 description 2
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 2
- 229940006607 hirudin Drugs 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- FWXIZVVTJVNNRX-UHFFFAOYSA-H iron(3+);oxalate;hexahydrate Chemical compound O.O.O.O.O.O.[Fe+3].[Fe+3].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O FWXIZVVTJVNNRX-UHFFFAOYSA-H 0.000 description 2
- FIBJDTSHOUXTKV-BRHMIFOHSA-N lepirudin Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)CNC2=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)[C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1)C(C)C)C(C)C)[C@@H](C)O)[C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O FIBJDTSHOUXTKV-BRHMIFOHSA-N 0.000 description 2
- 108010002230 lepirudin Proteins 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- WGOOPYYIMZJWMA-UHFFFAOYSA-N methyl 4-formyl-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(C=O)C([N+]([O-])=O)=C1 WGOOPYYIMZJWMA-UHFFFAOYSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- CZZKZDIEDHPDOQ-VOJFVSQTSA-N n-[(1s)-1-(4-chloropyridin-2-yl)but-3-enyl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](=O)N[C@@H](CC=C)C1=CC(Cl)=CC=N1 CZZKZDIEDHPDOQ-VOJFVSQTSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 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 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- UCUUFSAXZMGPGH-UHFFFAOYSA-N penta-1,4-dien-3-one Chemical compound C=CC(=O)C=C UCUUFSAXZMGPGH-UHFFFAOYSA-N 0.000 description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229940030915 refludan Drugs 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000003001 serine protease inhibitor Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 229960000187 tissue plasminogen activator Drugs 0.000 description 2
- 150000008648 triflates Chemical class 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 229960005080 warfarin Drugs 0.000 description 2
- 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 description 2
- 239000003643 water by type Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- CNXFNZDSEHVGEV-SSDOTTSWSA-N (1r)-1-(4-chloro-3-fluoropyridin-2-yl)but-3-en-1-ol Chemical compound C=CC[C@@H](O)C1=NC=CC(Cl)=C1F CNXFNZDSEHVGEV-SSDOTTSWSA-N 0.000 description 1
- DIRRKLFMHQUJCM-UHFFFAOYSA-N (2-aminophenyl)boronic acid Chemical compound NC1=CC=CC=C1B(O)O DIRRKLFMHQUJCM-UHFFFAOYSA-N 0.000 description 1
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- JNTASUHAFOHMQK-ZDUSSCGKSA-N (2s)-2-[(2-aminoacetyl)amino]-5-(diaminomethylideneamino)-n-(4-methyl-2-oxochromen-7-yl)pentanamide Chemical compound C1=C(NC(=O)[C@H](CCCN=C(N)N)NC(=O)CN)C=CC2=C1OC(=O)C=C2C JNTASUHAFOHMQK-ZDUSSCGKSA-N 0.000 description 1
- LJCBAPRMNYSDOP-LVCYMWGESA-N (2s)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;hydron;chloride;pentahydrate Chemical compound O.O.O.O.O.Cl.C1N(C(=N)C)CC[C@@H]1OC1=CC=C([C@H](CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 LJCBAPRMNYSDOP-LVCYMWGESA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- OJOFMLDBXPDXLQ-SECBINFHSA-N (4r)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-SECBINFHSA-N 0.000 description 1
- FFKHSXSLOYGVQT-DGCLKSJQSA-N (4r)-4-benzyl-3-[(2r)-2-methylbut-3-enoyl]-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N(C(=O)[C@@H](C=C)C)[C@@H]1CC1=CC=CC=C1 FFKHSXSLOYGVQT-DGCLKSJQSA-N 0.000 description 1
- FFKHSXSLOYGVQT-WCQYABFASA-N (4r)-4-benzyl-3-[(2s)-2-methylbut-3-enoyl]-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N(C(=O)[C@H](C=C)C)[C@@H]1CC1=CC=CC=C1 FFKHSXSLOYGVQT-WCQYABFASA-N 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- CBUYBRLMKVZECS-COSNYCCFSA-N (ne)-n-[(4-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](=O)\N=C\C1=CC(Cl)=CC=N1 CBUYBRLMKVZECS-COSNYCCFSA-N 0.000 description 1
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 description 1
- LSMWOQFDLBIYPM-UHFFFAOYSA-N 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-2h-imidazol-1-ium-2-ide Chemical group CC1=CC(C)=CC(C)=C1N1[C-]=[N+](C=2C(=CC(C)=CC=2C)C)CC1 LSMWOQFDLBIYPM-UHFFFAOYSA-N 0.000 description 1
- VDEAJFDASMTOOY-UHFFFAOYSA-N 1-(3-chloro-2,6-difluorophenyl)-2-methylprop-2-en-1-ol Chemical compound CC(=C)C(O)c1c(F)ccc(Cl)c1F VDEAJFDASMTOOY-UHFFFAOYSA-N 0.000 description 1
- BPQSPPRNACJWGK-UHFFFAOYSA-N 1-(3-chloro-2,6-difluorophenyl)-2-methylprop-2-en-1-one Chemical compound CC(=C)C(=O)C1=C(F)C=CC(Cl)=C1F BPQSPPRNACJWGK-UHFFFAOYSA-N 0.000 description 1
- QGVCLRNFMPRYIM-UHFFFAOYSA-N 1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one Chemical compound FC1=CC=C(Cl)C(F)=C1C(=O)C=C QGVCLRNFMPRYIM-UHFFFAOYSA-N 0.000 description 1
- CXGLBMMGBGRTAO-UHFFFAOYSA-N 1-(4-chloropyridin-2-yl)but-3-enyl carbamate Chemical compound C(N)(OC(CC=C)C1=NC=CC(=C1)Cl)=O CXGLBMMGBGRTAO-UHFFFAOYSA-N 0.000 description 1
- XVVVTDYZZMZPIY-UHFFFAOYSA-N 1-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-en-1-one Chemical compound FC1=C(Cl)C=CC(N2N=NN=C2)=C1C(=O)C=C XVVVTDYZZMZPIY-UHFFFAOYSA-N 0.000 description 1
- OQISSLMJTNLWIL-UHFFFAOYSA-N 1-[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]prop-2-en-1-one Chemical compound C=CC(=O)C1=CC(Cl)=CC=C1N1N=CN=C1 OQISSLMJTNLWIL-UHFFFAOYSA-N 0.000 description 1
- CQCMBXFDPVOARR-UHFFFAOYSA-N 1-[5-chloro-2-(triazol-1-yl)phenyl]prop-2-en-1-one Chemical compound C=CC(=O)C1=CC(Cl)=CC=C1N1N=NC=C1 CQCMBXFDPVOARR-UHFFFAOYSA-N 0.000 description 1
- AZIMWACVHNQVOB-UHFFFAOYSA-N 1-chloro-3-ethenyl-2,4-difluorobenzene Chemical compound FC1=CC=C(Cl)C(F)=C1C=C AZIMWACVHNQVOB-UHFFFAOYSA-N 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- AJXQJMZXUNSYKV-UHFFFAOYSA-N 2,3,3-trihydroxyoxane-2-carboxylic acid Chemical compound OC(=O)C1(O)OCCCC1(O)O AJXQJMZXUNSYKV-UHFFFAOYSA-N 0.000 description 1
- WDBAXYQUOZDFOJ-UHFFFAOYSA-N 2,3-difluorobenzaldehyde Chemical compound FC1=CC=CC(C=O)=C1F WDBAXYQUOZDFOJ-UHFFFAOYSA-N 0.000 description 1
- MDNDJMCSXOXBFZ-UHFFFAOYSA-N 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane Chemical compound O1CC(C)(C)COB1B1OCC(C)(C)CO1 MDNDJMCSXOXBFZ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- CLAKAYYJMKYMRC-UHFFFAOYSA-N 2-diethoxyphosphorylacetyl chloride Chemical compound CCOP(=O)(CC(Cl)=O)OCC CLAKAYYJMKYMRC-UHFFFAOYSA-N 0.000 description 1
- VQGJFXYTWXPKHV-UHFFFAOYSA-N 2-diethoxyphosphorylpropanoic acid Chemical compound CCOP(=O)(OCC)C(C)C(O)=O VQGJFXYTWXPKHV-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- VSFRGVVQJGKTEO-UHFFFAOYSA-N 3-(3-chloro-2,6-difluorophenyl)-2-hydroxy-2h-furan-5-one Chemical compound OC1OC(=O)C=C1C1=C(F)C=CC(Cl)=C1F VSFRGVVQJGKTEO-UHFFFAOYSA-N 0.000 description 1
- QONDAZCJAPQGRX-UHFFFAOYSA-N 3-benzylimidazole-4-carbaldehyde Chemical compound O=CC1=CN=CN1CC1=CC=CC=C1 QONDAZCJAPQGRX-UHFFFAOYSA-N 0.000 description 1
- IEQRWXTVPJYPFS-UHFFFAOYSA-N 3-chloro-2-fluoro-6-(tetrazol-1-yl)benzaldehyde Chemical compound FC1=C(Cl)C=CC(N2N=NN=C2)=C1C=O IEQRWXTVPJYPFS-UHFFFAOYSA-N 0.000 description 1
- PIEZXKIADRCNNE-UHFFFAOYSA-N 3-chloro-n-methoxy-n-methylbenzamide Chemical compound CON(C)C(=O)C1=CC=CC(Cl)=C1 PIEZXKIADRCNNE-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 1
- MFBYRZYOZKGQGD-UHFFFAOYSA-N 4-(1,3-dioxolan-2-yl)-3-nitrobenzoic acid Chemical compound [O-][N+](=O)C1=CC(C(=O)O)=CC=C1C1OCCO1 MFBYRZYOZKGQGD-UHFFFAOYSA-N 0.000 description 1
- NFGGDPYDUVFSCH-UHFFFAOYSA-N 4-chloro-3-fluoropyridine-2-carbaldehyde Chemical compound FC1=C(Cl)C=CN=C1C=O NFGGDPYDUVFSCH-UHFFFAOYSA-N 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- OFTMAPUSAKQMTN-SFHVURJKSA-N 5-(methoxycarbonylamino)-2-[2-[(1s)-1-[(2-methylpropan-2-yl)oxycarbonylamino]but-3-enyl]pyridin-4-yl]benzoic acid Chemical compound OC(=O)C1=CC(NC(=O)OC)=CC=C1C1=CC=NC([C@H](CC=C)NC(=O)OC(C)(C)C)=C1 OFTMAPUSAKQMTN-SFHVURJKSA-N 0.000 description 1
- ZOSBTTZWQJDLRU-UHFFFAOYSA-N 5-chloro-2-(3-methyl-1,2,4-triazol-1-yl)benzaldehyde Chemical compound N1=C(C)N=CN1C1=CC=C(Cl)C=C1C=O ZOSBTTZWQJDLRU-UHFFFAOYSA-N 0.000 description 1
- GZGNOVBNGJCXDQ-UHFFFAOYSA-N 5-chloro-2-(triazol-1-yl)benzaldehyde Chemical compound O=CC1=CC(Cl)=CC=C1N1N=NC=C1 GZGNOVBNGJCXDQ-UHFFFAOYSA-N 0.000 description 1
- PZKFSRWSQOQYNR-UHFFFAOYSA-N 5-methyl-1h-1,2,4-triazole Chemical compound CC1=NC=NN1 PZKFSRWSQOQYNR-UHFFFAOYSA-N 0.000 description 1
- ILJCPNFAFWGTAR-UHFFFAOYSA-N 6-bromo-3-chloro-2-fluorobenzaldehyde Chemical compound FC1=C(Cl)C=CC(Br)=C1C=O ILJCPNFAFWGTAR-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 1
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- HHHDMCKZLPKUKD-UHFFFAOYSA-N CC1(C)COBO1 Chemical compound CC1(C)COBO1 HHHDMCKZLPKUKD-UHFFFAOYSA-N 0.000 description 1
- DDXWTSVCCDJAMS-UHFFFAOYSA-N COP(=O)(OC)CC(=O)C(CC=C)NC(O)=O Chemical compound COP(=O)(OC)CC(=O)C(CC=C)NC(O)=O DDXWTSVCCDJAMS-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 108090000201 Carboxypeptidase B2 Proteins 0.000 description 1
- 102000003847 Carboxypeptidase B2 Human genes 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 102100026735 Coagulation factor VIII Human genes 0.000 description 1
- 108010048623 Collagen Receptors Proteins 0.000 description 1
- 102000009268 Collagen Receptors Human genes 0.000 description 1
- 102000055157 Complement C1 Inhibitor Human genes 0.000 description 1
- 108700040183 Complement C1 Inhibitor Proteins 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010056764 Eptifibatide Proteins 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 201000003542 Factor VIII deficiency Diseases 0.000 description 1
- 108010080865 Factor XII Proteins 0.000 description 1
- 102000000429 Factor XII Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010054964 H-hexahydrotyrosyl-alanyl-arginine-4-nitroanilide Proteins 0.000 description 1
- 229910003953 H3PO2 Inorganic materials 0.000 description 1
- 108010081348 HRT1 protein Hairy Proteins 0.000 description 1
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 1
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 description 1
- 208000009292 Hemophilia A Diseases 0.000 description 1
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 1
- 101001091365 Homo sapiens Plasma kallikrein Proteins 0.000 description 1
- 229940127517 Hormone Receptor Modulators Drugs 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 101710149643 Integrin alpha-IIb Proteins 0.000 description 1
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229910017906 NH3H2O Inorganic materials 0.000 description 1
- UDBUOOGIPPNOBB-LBPRGKRZSA-N N[C@@H](CC=C)C1=NC=CC(=C1)C1=C(C=NC=C1)N Chemical compound N[C@@H](CC=C)C1=NC=CC(=C1)C1=C(C=NC=C1)N UDBUOOGIPPNOBB-LBPRGKRZSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- TZRGEBDGMYOMHA-UHFFFAOYSA-N P(OCC)(OC(C(=O)Cl)C)=O Chemical compound P(OCC)(OC(C(=O)Cl)C)=O TZRGEBDGMYOMHA-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 101150053131 PTGER3 gene Proteins 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 206010034962 Photopsia Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 201000005660 Protein C Deficiency Diseases 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 102000016927 Purinergic P2Y1 Receptors Human genes 0.000 description 1
- 108010028935 Purinergic P2Y1 Receptors Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 102000003938 Thromboxane Receptors Human genes 0.000 description 1
- 108090000300 Thromboxane Receptors Proteins 0.000 description 1
- 206010053476 Traumatic haemorrhage Diseases 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- MRDJGFRQZHXGDI-UHFFFAOYSA-N [3-[(2-methylpropan-2-yl)oxycarbonylamino]pyridin-4-yl]boronic acid Chemical compound CC(C)(C)OC(=O)NC1=CN=CC=C1B(O)O MRDJGFRQZHXGDI-UHFFFAOYSA-N 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000004036 acetal group Chemical group 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 1
- RRUDCFGSUDOHDG-UHFFFAOYSA-N acetohydroxamic acid Chemical compound CC(O)=NO RRUDCFGSUDOHDG-UHFFFAOYSA-N 0.000 description 1
- 229960001171 acetohydroxamic acid Drugs 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- VITFJKNVGRZRKB-UHFFFAOYSA-N acetyl isothiocyanate Chemical compound CC(=O)N=C=S VITFJKNVGRZRKB-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 229960004601 aliskiren Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 239000000587 angiogenesis modulating agent Substances 0.000 description 1
- 229940076002 angiogenesis modulator Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940127090 anticoagulant agent Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 229960003886 apixaban Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 229940104697 arixtra Drugs 0.000 description 1
- XEPNJJFNSJKTSO-UHFFFAOYSA-N azanium;zinc;chloride Chemical compound [NH4+].[Cl-].[Zn] XEPNJJFNSJKTSO-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- IHIBPMKGKJSBKT-UHFFFAOYSA-N but-3-enyl carbamate Chemical compound NC(=O)OCCC=C IHIBPMKGKJSBKT-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 125000001108 carbamothioyl group Chemical group C(N)(=S)* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000007820 coagulation assay Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 208000011664 congenital factor XI deficiency Diseases 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- GTBRTGPZZALPNS-MXHVRSFHSA-N cyanoketone Chemical compound C1C=C2C(C)(C)C(=O)[C@H](C#N)C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GTBRTGPZZALPNS-MXHVRSFHSA-N 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- XSYZCZPCBXYQTE-UHFFFAOYSA-N cyclodecylcyclodecane Chemical compound C1CCCCCCCCC1C1CCCCCCCCC1 XSYZCZPCBXYQTE-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 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 description 1
- 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- XEKSTYNIJLDDAZ-JASSWCPGSA-D decasodium;(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5r,6r)-6-[(2r,3s,4s,5r,6r)-2-carboxylato-4-hydroxy-6-[(2r,3s,4r,5r,6s)-4-hydroxy-6-methoxy-5-(sulfonatoamino)-2-(sulfonatooxymethyl)oxan-3-yl]oxy-5-sulfonatooxyoxan-3-yl]oxy-5-(sulfonatoamino)-4-sulfonatooxy-2-(sul Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O[C@@H]1[C@@H](NS([O-])(=O)=O)[C@@H](OC)O[C@H](COS([O-])(=O)=O)[C@H]1O[C@H]1[C@H](OS([O-])(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS([O-])(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O4)NS([O-])(=O)=O)[C@H](O3)C([O-])=O)O)[C@@H](COS([O-])(=O)=O)O2)NS([O-])(=O)=O)[C@H](C([O-])=O)O1 XEKSTYNIJLDDAZ-JASSWCPGSA-D 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- OJVUNGKDLNJBTJ-UHFFFAOYSA-N dipotassium dioxido(trifluoromethoxy)borane Chemical compound [K+].[K+].[O-]B([O-])OC(F)(F)F OJVUNGKDLNJBTJ-UHFFFAOYSA-N 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- OEHFRZLKGRKFAS-UHFFFAOYSA-N droxicam Chemical compound C12=CC=CC=C2S(=O)(=O)N(C)C(C2=O)=C1OC(=O)N2C1=CC=CC=N1 OEHFRZLKGRKFAS-UHFFFAOYSA-N 0.000 description 1
- 229960001850 droxicam Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- GLGOPUHVAZCPRB-LROMGURASA-N eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CN=C2[C]1C=CC=C2 GLGOPUHVAZCPRB-LROMGURASA-N 0.000 description 1
- 229960004468 eptifibatide Drugs 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- PXBOIFNOMWXDFC-UHFFFAOYSA-M ethyl 2-pyridin-1-ium-1-ylacetate;bromide Chemical compound [Br-].CCOC(=O)C[N+]1=CC=CC=C1 PXBOIFNOMWXDFC-UHFFFAOYSA-M 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 201000007219 factor XI deficiency Diseases 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000010363 gene targeting Methods 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 239000003324 growth hormone secretagogue Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005221 halo alkyl carbonyl amino group Chemical group 0.000 description 1
- 208000009429 hemophilia B Diseases 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 208000013746 hereditary thrombophilia due to congenital protein C deficiency Diseases 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 210000003692 ilium Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000002530 ischemic preconditioning effect Effects 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 229940118179 lovenox Drugs 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- DQEUYIQDSMINEY-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C=C DQEUYIQDSMINEY-UHFFFAOYSA-M 0.000 description 1
- UZNGRHDUJIVHQT-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].C[C-]=C UZNGRHDUJIVHQT-UHFFFAOYSA-M 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229940103185 mefenamate Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- DKWNMCUOEDMMIN-PKOBYXMFSA-N melagatran Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@H](NCC(O)=O)C2CCCCC2)CC1 DKWNMCUOEDMMIN-PKOBYXMFSA-N 0.000 description 1
- 229960002137 melagatran Drugs 0.000 description 1
- LFEMIJOAJLTUHL-SFHVURJKSA-N methyl 2-[2-[(1S)-1-[(2-methylpropan-2-yl)oxycarbonylamino]but-3-enyl]pyridin-4-yl]-5-nitrobenzoate Chemical compound COC(=O)C1=CC([N+]([O-])=O)=CC=C1C1=CC=NC([C@H](CC=C)NC(=O)OC(C)(C)C)=C1 LFEMIJOAJLTUHL-SFHVURJKSA-N 0.000 description 1
- VSEYYEKRZNRECT-UHFFFAOYSA-N methyl 2-bromo-5-nitrobenzoate Chemical compound COC(=O)C1=CC([N+]([O-])=O)=CC=C1Br VSEYYEKRZNRECT-UHFFFAOYSA-N 0.000 description 1
- LXGXMBLBCUSHAJ-UHFFFAOYSA-N methyl 4-(1,3-dioxolan-2-yl)-3-nitrobenzoate Chemical compound [O-][N+](=O)C1=CC(C(=O)OC)=CC=C1C1OCCO1 LXGXMBLBCUSHAJ-UHFFFAOYSA-N 0.000 description 1
- COWLHIOGHYYNNH-IBGZPJMESA-N methyl 5-(methoxycarbonylamino)-2-[2-[(1S)-1-[(2-methylpropan-2-yl)oxycarbonylamino]but-3-enyl]pyridin-4-yl]benzoate Chemical compound COC(=O)C1=CC(NC(=O)OC)=CC=C1C1=CC=NC([C@H](CC=C)NC(=O)OC(C)(C)C)=C1 COWLHIOGHYYNNH-IBGZPJMESA-N 0.000 description 1
- AZFQCTBZOPUVOW-UHFFFAOYSA-N methyl(triphenyl)phosphanium Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 AZFQCTBZOPUVOW-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000002394 mineralocorticoid antagonist Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical group [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000002089 myocardial stunning Diseases 0.000 description 1
- VYNKVNDKAOGAAQ-RUZDIDTESA-N n-[(1r)-2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-1-phenylethyl]-1h-indole-6-carboxamide Chemical compound C1CN(C)CCC1N1CCN(C(=O)[C@H](NC(=O)C=2C=C3NC=CC3=CC=2)C=2C=CC=CC=2)CC1 VYNKVNDKAOGAAQ-RUZDIDTESA-N 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- NALNTVTXRGWALV-UHFFFAOYSA-N n-methoxy-n,3-dimethylcyclohexane-1-carboxamide Chemical compound CON(C)C(=O)C1CCCC(C)C1 NALNTVTXRGWALV-UHFFFAOYSA-N 0.000 description 1
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 229910000065 phosphene Inorganic materials 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 239000002570 phosphodiesterase III inhibitor Substances 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- 230000033885 plasminogen activation Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229940125422 potassium channel blocker Drugs 0.000 description 1
- 239000003450 potassium channel blocker Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012041 precatalyst Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000019 pro-fibrinolytic effect Effects 0.000 description 1
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229960001148 rivaroxaban Drugs 0.000 description 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
- RADGOBKLTHEUQO-UHFFFAOYSA-N ruthenium(4+) Chemical compound [Ru+4] RADGOBKLTHEUQO-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229940071182 stannate Drugs 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- WHTJYQJYZDHCBS-KRWDZBQOSA-N tert-butyl n-[(1s)-1-[4-(2-aminophenyl)pyridin-2-yl]but-3-enyl]carbamate Chemical compound C1=NC([C@H](CC=C)NC(=O)OC(C)(C)C)=CC(C=2C(=CC=CC=2)N)=C1 WHTJYQJYZDHCBS-KRWDZBQOSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- BGYOMDCFESEAAI-GFCCVEGCSA-N tert-butyl-[(1r)-1-(4-chloro-3-fluoropyridin-2-yl)but-3-enoxy]-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[C@H](CC=C)C1=NC=CC(Cl)=C1F BGYOMDCFESEAAI-GFCCVEGCSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 208000014173 thrombophilia due to thrombin defect Diseases 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- 229960003425 tirofiban Drugs 0.000 description 1
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- CCZXMDQFIVMWMF-UHFFFAOYSA-N trifluoromethoxyboronic acid Chemical compound OB(O)OC(F)(F)F CCZXMDQFIVMWMF-UHFFFAOYSA-N 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- ZXIBCJHYVWYIKI-PZJWPPBQSA-N ximelagatran Chemical compound C1([C@@H](NCC(=O)OCC)C(=O)N2[C@@H](CC2)C(=O)NCC=2C=CC(=CC=2)C(\N)=N\O)CCCCC1 ZXIBCJHYVWYIKI-PZJWPPBQSA-N 0.000 description 1
- 229960001522 ximelagatran Drugs 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/16—Halogenated acetic acids
- C07C53/18—Halogenated acetic acids containing fluorine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261679197P | 2012-08-03 | 2012-08-03 | |
| US201261679197P | 2012-08-03 | ||
| US201361787081P | 2013-03-15 | 2013-03-15 | |
| US201361787081P | 2013-03-15 | ||
| PCT/US2013/053416 WO2014022767A1 (en) | 2012-08-03 | 2013-08-02 | Dihydropyridone p1 as factor xia inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2623175T3 true ES2623175T3 (es) | 2017-07-10 |
Family
ID=48949290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES13747625.5T Active ES2623175T3 (es) | 2012-08-03 | 2013-08-02 | Dihidropiridona P1 como inhibidores del factor XIA |
Country Status (27)
| Country | Link |
|---|---|
| US (2) | US9409908B2 (enExample) |
| EP (1) | EP2880026B1 (enExample) |
| JP (1) | JP6082463B2 (enExample) |
| KR (1) | KR20150038372A (enExample) |
| CN (2) | CN108250199B (enExample) |
| AR (1) | AR091981A1 (enExample) |
| AU (1) | AU2013296259A1 (enExample) |
| BR (1) | BR112015002081A2 (enExample) |
| CA (1) | CA2880866A1 (enExample) |
| CY (1) | CY1119004T1 (enExample) |
| DK (1) | DK2880026T3 (enExample) |
| EA (1) | EA028581B1 (enExample) |
| ES (1) | ES2623175T3 (enExample) |
| HR (1) | HRP20170506T1 (enExample) |
| HU (1) | HUE032622T2 (enExample) |
| IL (1) | IL237011A0 (enExample) |
| LT (1) | LT2880026T (enExample) |
| MX (1) | MX361759B (enExample) |
| PL (1) | PL2880026T3 (enExample) |
| PT (1) | PT2880026T (enExample) |
| RS (1) | RS55975B1 (enExample) |
| SG (1) | SG11201500271UA (enExample) |
| SI (1) | SI2880026T1 (enExample) |
| SM (1) | SMT201700240T1 (enExample) |
| TW (1) | TW201410667A (enExample) |
| UY (1) | UY34960A (enExample) |
| WO (1) | WO2014022767A1 (enExample) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201311689A (zh) | 2011-08-05 | 2013-03-16 | 必治妥美雅史谷比公司 | 作為因子ｘｉａ抑制劑之新穎巨環化合物 |
| TW201319068A (zh) | 2011-08-05 | 2013-05-16 | 必治妥美雅史谷比公司 | 作為ｘｉａ因子抑制劑之環狀ｐ１接合劑 |
| JP6033317B2 (ja) | 2011-10-14 | 2016-11-30 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 第ｘｉａ因子阻害剤としての置換テトラヒドロイソキノリン化合物 |
| EP2766347B1 (en) | 2011-10-14 | 2016-05-04 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| UY34393A (es) | 2011-10-14 | 2013-04-30 | Bristol Myers Squibb Company Una Corporacion Del Estado De Delaware | Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor xia |
| US9403774B2 (en) | 2012-10-12 | 2016-08-02 | Bristol-Myers Squibb Company | Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| WO2014059202A1 (en) | 2012-10-12 | 2014-04-17 | Bristol-Myers Squibb Company | Guanidine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| EA032092B1 (ru) | 2012-10-12 | 2019-04-30 | Бристол-Майерс Сквибб Компани | Кристаллические формы ингибитора фактора xia |
| EP2978751B1 (en) | 2013-03-25 | 2018-12-05 | Bristol-Myers Squibb Company | Tetrahydroisoquinolines containing substituted azoles as factor xia inhibitors |
| FR3010076B1 (fr) * | 2013-09-02 | 2016-12-23 | Centre Nat De La Rech Scient - Cnrs - | Inhibiteurs de metalloproteases, leurs procedes de preparation et leurs utilisations therapeutiques |
| UY35971A (es) * | 2014-01-31 | 2015-07-31 | Bristol Myers Squibb Company Una Corporación Del Estado De Delaware | Macrociclos con grupos p2? aromáticos como inhibidores del factor xia |
| NO2760821T3 (enExample) | 2014-01-31 | 2018-03-10 | ||
| CN107074821B (zh) | 2014-09-04 | 2020-05-22 | 百时美施贵宝公司 | 为fxia抑制剂的二酰胺大环化合物 |
| US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
| NO2721243T3 (enExample) * | 2014-10-01 | 2018-10-20 | ||
| CN108026083B (zh) * | 2015-06-19 | 2021-08-27 | 百时美施贵宝公司 | 作为因子xia抑制剂的二酰胺大环 |
| JO3703B1 (ar) * | 2015-07-09 | 2021-01-31 | Bayer Pharma AG | مشتقات أوكسوبيريدين مستبدلة |
| EP3868753B1 (en) * | 2015-07-29 | 2022-12-21 | Bristol-Myers Squibb Company | Factor xia macrocyclic inhibitors bearing a non-aromatic p2' group |
| JP6629958B2 (ja) * | 2015-07-29 | 2020-01-15 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | アルキルまたはシクロアルキルＰ２’基を担持する大員環の第ＸＩａ因子阻害剤 |
| KR102697816B1 (ko) * | 2015-08-05 | 2024-08-21 | 브리스톨-마이어스 스큅 컴퍼니 | 신규 치환된 글리신 유도된 fxia 억제제 |
| MA43128A (fr) * | 2015-10-29 | 2018-09-05 | Merck Sharp & Dohme | Inhibiteurs du facteur xia |
| EP3371162B1 (en) | 2015-10-29 | 2022-01-26 | Merck Sharp & Dohme Corp. | Macrocyclic spirocarbamate derivatives as factor xia inhibitors, pharmaceutically acceptable compositions and their use |
| US10752641B2 (en) | 2016-03-02 | 2020-08-25 | Bristol-Myers Squibb Company | Diamide macrocycles having factor XIa inhibiting activity |
| US10143681B2 (en) | 2016-08-22 | 2018-12-04 | Merck Sharp & Dohme Corp. | Factor XIa inhibitors |
| WO2018133793A1 (zh) * | 2017-01-18 | 2018-07-26 | 广东东阳光药业有限公司 | 凝血因子XIa抑制剂及其用途 |
| WO2019011166A1 (zh) * | 2017-07-14 | 2019-01-17 | 四川科伦博泰生物医药股份有限公司 | 大环酰胺化合物及其药物组合物和用途 |
| AU2020257911B2 (en) | 2019-04-16 | 2023-01-05 | China Resources Biopharmaceutical Company Limited | Macrocyclic derivatives acting as XIa factor inhibitor |
| US20220281868A1 (en) * | 2019-07-23 | 2022-09-08 | Medshine Discovery Inc. | Macrocyclic derivatives as factor xia inhibitors |
| CN113004284B (zh) * | 2019-12-20 | 2022-08-12 | 成都康弘药业集团股份有限公司 | 作为血浆激肽释放酶抑制剂的四环类化合物及其用途 |
| WO2021121396A1 (zh) * | 2019-12-20 | 2021-06-24 | 成都康弘药业集团股份有限公司 | 作为血浆激肽释放酶抑制剂的三环类化合物及其用途 |
| US20230312560A1 (en) * | 2020-07-22 | 2023-10-05 | Janssen Pharmaceutica Nv | Compounds useful as factor xia inhibitors |
| CN119894901A (zh) * | 2023-06-30 | 2025-04-25 | 深圳信立泰药业股份有限公司 | 一种多取代的大环化合物及其制备方法与应用 |
Family Cites Families (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3065190D1 (en) | 1979-11-05 | 1983-11-10 | Beecham Group Plc | Enzyme derivatives, and their preparation |
| PE121699A1 (es) | 1997-02-18 | 1999-12-08 | Boehringer Ingelheim Pharma | Heterociclos biciclicos disustituidos como inhibidores de la trombina |
| ZA985247B (en) | 1997-06-19 | 1999-12-17 | Du Pont Merck Pharma | Guanidine mimics as factor Xa inhibitors. |
| AU5546000A (en) | 1999-06-14 | 2001-01-02 | Protherics Molecular Design Limited | Compounds |
| DE19962924A1 (de) | 1999-12-24 | 2001-07-05 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
| AR035216A1 (es) | 2000-12-01 | 2004-05-05 | Astrazeneca Ab | Derivados de acido mandelico ,derivados farmaceuticamente aceptables, uso de estos derivados para la fabricacion de medicamentos, metodos de tratamiento ,procesos para la preparacion de estos derivados, y compuestos intermediarios |
| HRP20080382A2 (en) | 2001-09-21 | 2008-12-31 | Bristol-Myers Squibb Company A Delaware (Usa) Corporation | LACTAM-CONTAINING COMPOUNDS AND DERIVATIVES THEREOF AS FACTOR Xa INHIBITORS |
| US20040180855A1 (en) | 2003-02-19 | 2004-09-16 | Schumacher William A. | Methods of treating thrombosis with reduced risk of increased bleeding times |
| US7138412B2 (en) | 2003-03-11 | 2006-11-21 | Bristol-Myers Squibb Company | Tetrahydroquinoline derivatives useful as serine protease inhibitors |
| US7129264B2 (en) | 2003-04-16 | 2006-10-31 | Bristol-Myers Squibb Company | Biarylmethyl indolines and indoles as antithromboembolic agents |
| US7417063B2 (en) | 2004-04-13 | 2008-08-26 | Bristol-Myers Squibb Company | Bicyclic heterocycles useful as serine protease inhibitors |
| US7429604B2 (en) | 2004-06-15 | 2008-09-30 | Bristol Myers Squibb Company | Six-membered heterocycles useful as serine protease inhibitors |
| US7453002B2 (en) | 2004-06-15 | 2008-11-18 | Bristol-Myers Squibb Company | Five-membered heterocycles useful as serine protease inhibitors |
| CN101137412B (zh) | 2005-01-13 | 2012-11-07 | 布里斯托尔-迈尔斯·斯奎布公司 | 用作凝血因子XIa抑制剂的取代的二芳基化合物 |
| WO2006089005A2 (en) | 2005-02-17 | 2006-08-24 | Bristol-Myers Squibb Company | Combination of selective factor viia and/or xia and plasma kallikrein inhibitors |
| US8466295B2 (en) | 2005-12-14 | 2013-06-18 | Bristol-Myers Squibb Company | Thiophene derivatives as factor XIa inhibitors |
| US8163749B2 (en) | 2005-12-14 | 2012-04-24 | Bristol-Myers Squibb Company | Six-membered heterocycles useful as serine protease inhibitors |
| NZ568595A (en) | 2005-12-14 | 2010-04-30 | Bristol Myers Squibb Co | Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor Xla inhibitors |
| US8410155B2 (en) | 2006-12-15 | 2013-04-02 | Bristol-Myers Squibb Company | Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIA inhibitors |
| PE20081775A1 (es) * | 2006-12-20 | 2008-12-18 | Bristol Myers Squibb Co | Compuestos macrociclicos como inhibidores del factor viia |
| MX2009012847A (es) | 2007-06-13 | 2009-12-08 | Bristol Myers Squibb Co | Analogos dipeptidicos como inhibidores de factores de coagulacion. |
| ATE543811T1 (de) | 2008-03-13 | 2012-02-15 | Bristol Myers Squibb Co | Pyridazinderivate als faktor-xia-inhibitoren |
| KR101843542B1 (ko) * | 2010-02-11 | 2018-03-30 | 브리스톨-마이어스 스큅 컴퍼니 | 인자 ＸＩａ 억제제로서의 마크로사이클 |
| TW201311689A (zh) * | 2011-08-05 | 2013-03-16 | 必治妥美雅史谷比公司 | 作為因子ｘｉａ抑制劑之新穎巨環化合物 |
| TW201319068A (zh) | 2011-08-05 | 2013-05-16 | 必治妥美雅史谷比公司 | 作為ｘｉａ因子抑制劑之環狀ｐ１接合劑 |
| UY34393A (es) | 2011-10-14 | 2013-04-30 | Bristol Myers Squibb Company Una Corporacion Del Estado De Delaware | Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor xia |
| EP2766347B1 (en) | 2011-10-14 | 2016-05-04 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| JP6033317B2 (ja) | 2011-10-14 | 2016-11-30 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 第ｘｉａ因子阻害剤としての置換テトラヒドロイソキノリン化合物 |
| ES2765891T3 (es) | 2011-12-21 | 2020-06-11 | Ono Pharmaceutical Co | Derivados de piridinona y pirimidinona como inhibidores del factor XIa |
| JP2015083542A (ja) | 2012-02-08 | 2015-04-30 | 大日本住友製薬株式会社 | ３位置換プロリン誘導体 |
| GB201209138D0 (en) | 2012-05-24 | 2012-07-04 | Ono Pharmaceutical Co | Compounds |
-
2013
- 2013-08-02 BR BR112015002081A patent/BR112015002081A2/pt active Search and Examination
- 2013-08-02 JP JP2015525622A patent/JP6082463B2/ja active Active
- 2013-08-02 SI SI201330570A patent/SI2880026T1/sl unknown
- 2013-08-02 DK DK13747625.5T patent/DK2880026T3/en active
- 2013-08-02 AR ARP130102764A patent/AR091981A1/es unknown
- 2013-08-02 MX MX2015000892A patent/MX361759B/es active IP Right Grant
- 2013-08-02 WO PCT/US2013/053416 patent/WO2014022767A1/en not_active Ceased
- 2013-08-02 KR KR1020157004963A patent/KR20150038372A/ko not_active Withdrawn
- 2013-08-02 ES ES13747625.5T patent/ES2623175T3/es active Active
- 2013-08-02 CN CN201810051705.4A patent/CN108250199B/zh active Active
- 2013-08-02 AU AU2013296259A patent/AU2013296259A1/en not_active Abandoned
- 2013-08-02 SM SM20170240T patent/SMT201700240T1/it unknown
- 2013-08-02 TW TW102127905A patent/TW201410667A/zh unknown
- 2013-08-02 US US14/419,002 patent/US9409908B2/en active Active
- 2013-08-02 PT PT137476255T patent/PT2880026T/pt unknown
- 2013-08-02 UY UY0001034960A patent/UY34960A/es unknown
- 2013-08-02 RS RS20170501A patent/RS55975B1/sr unknown
- 2013-08-02 CA CA2880866A patent/CA2880866A1/en not_active Abandoned
- 2013-08-02 HR HRP20170506TT patent/HRP20170506T1/hr unknown
- 2013-08-02 EA EA201590277A patent/EA028581B1/ru not_active IP Right Cessation
- 2013-08-02 LT LTEP13747625.5T patent/LT2880026T/lt unknown
- 2013-08-02 SG SG11201500271UA patent/SG11201500271UA/en unknown
- 2013-08-02 CN CN201380040942.6A patent/CN104507924B/zh active Active
- 2013-08-02 EP EP13747625.5A patent/EP2880026B1/en active Active
- 2013-08-02 HU HUE13747625A patent/HUE032622T2/en unknown
- 2013-08-02 PL PL13747625T patent/PL2880026T3/pl unknown
-
2015
- 2015-01-29 IL IL237011A patent/IL237011A0/en unknown
-
2016
- 2016-07-08 US US15/205,059 patent/US9951071B2/en active Active
-
2017
- 2017-05-09 CY CY20171100499T patent/CY1119004T1/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2623175T3 (es) | Dihidropiridona P1 como inhibidores del factor XIA | |
| JP6630004B2 (ja) | 芳香族ｐ２’基を有する第ｘｉａ因子阻害剤としてのマクロ環 | |
| ES2733096T3 (es) | Intermediarios para la síntesis de ligadores P1 cíclicos como inhibidores del factor XIA | |
| ES2836270T3 (es) | Pirimidinonas como inhibidores del Factor XIa | |
| ES2605824T3 (es) | Dihidropiridona como inhibidores del factor XIa | |
| ES2380648T3 (es) | Derivados de piridazina como inhibidores del factor XIA | |
| JP6419836B2 (ja) | ヘテロサイクルと縮合した大環状第ｘｉａ因子阻害剤 | |
| KR20180031037A (ko) | 신규 치환된 글리신 유도된 fxia 억제제 | |
| KR20180030912A (ko) | 알킬 또는 시클로알킬 P2' 모이어티를 갖는 인자 XIa 마크로시클릭 억제제 | |
| KR102729666B1 (ko) | 비-방향족 P2' 기를 갖는 인자 XIa 신규 마크로사이클 |