ZA200110558B - Tricyclic compounds having spiro union. - Google Patents

Info

Publication number

ZA200110558B

ZA200110558B ZA200110558A ZA200110558A ZA200110558B ZA 200110558 B ZA200110558 B ZA 200110558B ZA 200110558 A ZA200110558 A ZA 200110558A ZA 200110558 A ZA200110558 A ZA 200110558A ZA 200110558 B ZA200110558 B ZA 200110558B

Authority

ZA

South Africa

Prior art keywords

group

compound

diaza

piperidin

bicyclo

Prior art date

1999-06-30

Links

• Espacenet
• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims description 891
• 125000003003 spiro group Chemical group 0.000 title claims description 35
• 150000003839 salts Chemical class 0.000 claims description 222
• 238000000034 method Methods 0.000 claims description 189
• -1 6-chloronaphthalen-2-ylsulfonyl Chemical group 0.000 claims description 150
• 125000000217 alkyl group Chemical group 0.000 claims description 144
• 239000000203 mixture Substances 0.000 claims description 140
• VRQDPNKOUPEWOC-UHFFFAOYSA-N spiro[bicyclo[2.2.2]octane-3,3'-piperidine] Chemical compound C1CCNCC21C(CC1)CCC1C2 VRQDPNKOUPEWOC-UHFFFAOYSA-N 0.000 claims description 131
• 125000001424 substituent group Chemical group 0.000 claims description 107
• 239000003112 inhibitor Substances 0.000 claims description 73
• 230000002401 inhibitory effect Effects 0.000 claims description 72
• 125000005843 halogen group Chemical group 0.000 claims description 50
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 49
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 49
• 229920006395 saturated elastomer Polymers 0.000 claims description 49
• 125000003545 alkoxy group Chemical group 0.000 claims description 43
• 125000000623 heterocyclic group Chemical group 0.000 claims description 41
• 125000002947 alkylene group Chemical group 0.000 claims description 40
• 230000002209 hydrophobic effect Effects 0.000 claims description 36
• 125000003277 amino group Chemical group 0.000 claims description 33
• 229910052757 nitrogen Inorganic materials 0.000 claims description 30
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 28
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 24
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 23
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 19
• 230000003993 interaction Effects 0.000 claims description 18
• 125000006239 protecting group Chemical group 0.000 claims description 18
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 17
• 125000004076 pyridyl group Chemical group 0.000 claims description 17
• 230000036961 partial effect Effects 0.000 claims description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims description 15
• 239000013078 crystal Substances 0.000 claims description 14
• 230000001747 exhibiting effect Effects 0.000 claims description 11
• 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 11
• 238000004166 bioassay Methods 0.000 claims description 9
• 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 9
• 108090000317 Chymotrypsin Proteins 0.000 claims description 8
• 229960002376 chymotrypsin Drugs 0.000 claims description 8
• 239000012634 fragment Substances 0.000 claims description 8
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 7
• 230000003287 optical effect Effects 0.000 claims description 7
• QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 6
• 125000000539 amino acid group Chemical group 0.000 claims description 6
• 150000001413 amino acids Chemical class 0.000 claims description 6
• 229910052698 phosphorus Inorganic materials 0.000 claims description 6
• ATVLKVRIWUZBSN-UHFFFAOYSA-N spiro[3,3a,5,6,7,7a-hexahydro-1H-indene-2,4'-piperidine]-4-one Chemical compound C1C2C(=O)CCCC2CC21CCNCC2 ATVLKVRIWUZBSN-UHFFFAOYSA-N 0.000 claims description 6
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 5
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
• 238000003556 assay Methods 0.000 claims description 5
• 230000005764 inhibitory process Effects 0.000 claims description 5
• 241000124008 Mammalia Species 0.000 claims description 4
• 150000007942 carboxylates Chemical class 0.000 claims description 3
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
• NRWRNGAIXQYSKM-UHFFFAOYSA-N 7-(6-chloronaphthalen-2-yl)sulfonyl-1'-pyridin-4-ylspiro[3,6,8,8a-tetrahydro-[1,3]oxazolo[3,2-a]pyrazine-2,4'-piperidine]-5-one Chemical compound C1=CC2=CC(Cl)=CC=C2C=C1S(=O)(=O)N(CC(=O)N1C2)CC1OC2(CC1)CCN1C1=CC=NC=C1 NRWRNGAIXQYSKM-UHFFFAOYSA-N 0.000 claims 1
• GNXLMCCZZCSKGL-UHFFFAOYSA-N 7-(6-chloronaphthalen-2-yl)sulfonyl-8a-(methoxymethyl)-1-methyl-1'-pyridin-4-ylspiro[6,8-dihydro-3h-imidazo[1,2-a]pyrazine-2,4'-piperidine]-5-one Chemical compound CN1C2(COC)CN(S(=O)(=O)C=3C=C4C=CC(Cl)=CC4=CC=3)CC(=O)N2CC1(CC1)CCN1C1=CC=NC=C1 GNXLMCCZZCSKGL-UHFFFAOYSA-N 0.000 claims 1
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 1
• 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
• 239000000651 prodrug Substances 0.000 claims 1
• 229940002612 prodrug Drugs 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 388
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 257
• 230000015572 biosynthetic process Effects 0.000 description 218
• 238000003786 synthesis reaction Methods 0.000 description 218
• 239000000243 solution Substances 0.000 description 141
• 239000002904 solvent Substances 0.000 description 120
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 100
• 230000002829 reductive effect Effects 0.000 description 99
• 238000006243 chemical reaction Methods 0.000 description 97
• 239000011541 reaction mixture Substances 0.000 description 88
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 86
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
• 238000004519 manufacturing process Methods 0.000 description 71
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 64
• 239000003480 eluent Substances 0.000 description 63
• 238000010898 silica gel chromatography Methods 0.000 description 61
• 238000001816 cooling Methods 0.000 description 60
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 53
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 51
• 239000012044 organic layer Substances 0.000 description 51
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 48
• 125000006615 aromatic heterocyclic group Chemical group 0.000 description 45
• 230000008569 process Effects 0.000 description 45
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 44
• 239000007864 aqueous solution Substances 0.000 description 44
• 239000003814 drug Substances 0.000 description 44
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
• 125000003118 aryl group Chemical group 0.000 description 43
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
• 238000010992 reflux Methods 0.000 description 35
• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 32
• 238000012360 testing method Methods 0.000 description 30
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 29
• 238000004896 high resolution mass spectrometry Methods 0.000 description 29
• 238000003756 stirring Methods 0.000 description 28
• XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 description 27
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 26
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
• 125000004429 atom Chemical group 0.000 description 25
• 230000003647 oxidation Effects 0.000 description 25
• 238000007254 oxidation reaction Methods 0.000 description 25
• 229940079593 drug Drugs 0.000 description 24
• 235000019441 ethanol Nutrition 0.000 description 24
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 24
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
• 235000017557 sodium bicarbonate Nutrition 0.000 description 24
• 239000003795 chemical substances by application Substances 0.000 description 22
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 21
• 125000002252 acyl group Chemical group 0.000 description 21
• 125000003342 alkenyl group Chemical group 0.000 description 21
• 125000004432 carbon atom Chemical group C* 0.000 description 21
• 201000010099 disease Diseases 0.000 description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
• 239000000725 suspension Substances 0.000 description 21
• 125000004043 oxo group Chemical group O=* 0.000 description 20
• 239000002253 acid Substances 0.000 description 19
• 238000001914 filtration Methods 0.000 description 19
• 125000005842 heteroatom Chemical group 0.000 description 19
• 238000006467 substitution reaction Methods 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 18
• 230000015271 coagulation Effects 0.000 description 17
• 238000005345 coagulation Methods 0.000 description 17
• 229960004132 diethyl ether Drugs 0.000 description 17
• 229910052717 sulfur Inorganic materials 0.000 description 17
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 16
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 16
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
• 230000000704 physical effect Effects 0.000 description 16
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• 239000003146 anticoagulant agent Substances 0.000 description 15
• FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 15
• 125000002950 monocyclic group Chemical group 0.000 description 15
• 125000004434 sulfur atom Chemical group 0.000 description 15
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
• WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 14
• 229940127219 anticoagulant drug Drugs 0.000 description 14
• 230000000694 effects Effects 0.000 description 14
• 229910052739 hydrogen Inorganic materials 0.000 description 14
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 14
• 125000000304 alkynyl group Chemical group 0.000 description 13
• 125000004093 cyano group Chemical group *C#N 0.000 description 13
• 238000013461 design Methods 0.000 description 13
• 125000003710 aryl alkyl group Chemical group 0.000 description 12
• 239000010410 layer Substances 0.000 description 12
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 12
• 230000003449 preventive effect Effects 0.000 description 12
• 230000000069 prophylactic effect Effects 0.000 description 12
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
• 208000007536 Thrombosis Diseases 0.000 description 11
• 125000000392 cycloalkenyl group Chemical group 0.000 description 11
• 229910052736 halogen Inorganic materials 0.000 description 11
• 150000002367 halogens Chemical class 0.000 description 11
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
• 108090000190 Thrombin Proteins 0.000 description 10
• HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 10
• 125000004122 cyclic group Chemical group 0.000 description 10
• 239000001257 hydrogen Substances 0.000 description 10
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
• 229940124597 therapeutic agent Drugs 0.000 description 10
• 229960004072 thrombin Drugs 0.000 description 10
• 229910052721 tungsten Inorganic materials 0.000 description 10
• 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 10
• 229960005080 warfarin Drugs 0.000 description 10
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• 102000004190 Enzymes Human genes 0.000 description 9
• 108090000790 Enzymes Proteins 0.000 description 9
• 208000032843 Hemorrhage Diseases 0.000 description 9
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
• 208000034158 bleeding Diseases 0.000 description 9
• 230000000740 bleeding effect Effects 0.000 description 9
• 229910052801 chlorine Inorganic materials 0.000 description 9
• 229940088598 enzyme Drugs 0.000 description 9
• 239000000706 filtrate Substances 0.000 description 9
• 150000002430 hydrocarbons Chemical group 0.000 description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
• 239000007858 starting material Substances 0.000 description 9
• 239000000758 substrate Substances 0.000 description 9
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
• 208000005189 Embolism Diseases 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
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
• 102000012479 Serine Proteases Human genes 0.000 description 8
• 108010022999 Serine Proteases Proteins 0.000 description 8
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
• 238000010521 absorption reaction Methods 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 238000011161 development Methods 0.000 description 8
• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 8
• FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 8
• 229960002897 heparin Drugs 0.000 description 8
• 229920000669 heparin Polymers 0.000 description 8
• NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
• KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 8
• 229910000027 potassium carbonate Inorganic materials 0.000 description 8
• 230000002265 prevention Effects 0.000 description 8
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
• 125000003282 alkyl amino group Chemical group 0.000 description 7
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 7
• 239000008280 blood Substances 0.000 description 7
• 210000004369 blood Anatomy 0.000 description 7
• 239000003054 catalyst Substances 0.000 description 7
• QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 7
• 230000009881 electrostatic interaction Effects 0.000 description 7
• 229940102223 injectable solution Drugs 0.000 description 7
• 238000005259 measurement Methods 0.000 description 7
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 7
• 229910052760 oxygen Inorganic materials 0.000 description 7
• 238000012216 screening Methods 0.000 description 7
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
• 229940122388 Thrombin inhibitor Drugs 0.000 description 6
• 235000011054 acetic acid Nutrition 0.000 description 6
• 125000005115 alkyl carbamoyl group Chemical group 0.000 description 6
• 229910052799 carbon Inorganic materials 0.000 description 6
• 125000001309 chloro group Chemical group Cl* 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 238000004590 computer program Methods 0.000 description 6
• 238000010908 decantation Methods 0.000 description 6
• 238000000605 extraction Methods 0.000 description 6
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
• 239000004615 ingredient Substances 0.000 description 6
• 230000000302 ischemic effect Effects 0.000 description 6
• 239000008101 lactose Substances 0.000 description 6
• 229910052751 metal Inorganic materials 0.000 description 6
• 239000002184 metal Substances 0.000 description 6
• 239000011259 mixed solution Substances 0.000 description 6
• 230000003389 potentiating effect Effects 0.000 description 6
• 239000000047 product Substances 0.000 description 6
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 6
• 230000009467 reduction Effects 0.000 description 6
• 238000006722 reduction reaction Methods 0.000 description 6
• 239000006228 supernatant Substances 0.000 description 6
• 125000003396 thiol group Chemical class [H]S* 0.000 description 6
• 239000003868 thrombin inhibitor Substances 0.000 description 6
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