JP4939401B2 - ＴＡＦＩａ阻害剤として用いるイミダゾール誘導体 - Google Patents

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Publication number

JP4939401B2

JP4939401B2 JP2007508756A JP2007508756A JP4939401B2 JP 4939401 B2 JP4939401 B2 JP 4939401B2 JP 2007508756 A JP2007508756 A JP 2007508756A JP 2007508756 A JP2007508756 A JP 2007508756A JP 4939401 B2 JP4939401 B2 JP 4939401B2

Authority

JP

Japan

Prior art keywords

imidazol

alkyl

unsubstituted

twice

once

Prior art date

2004-04-22

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.)

Expired - Fee Related

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• 239000003112 inhibitor Substances 0.000 title description 18
• 150000002460 imidazoles Chemical class 0.000 title 1
• 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 177
• -1 aminopyridyl Chemical group 0.000 claims description 117
• 238000000034 method Methods 0.000 claims description 101
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 49
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 46
• 239000000203 mixture Substances 0.000 claims description 44
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
• 150000003839 salts Chemical class 0.000 claims description 31
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
• 239000000460 chlorine Substances 0.000 claims description 26
• 238000004587 chromatography analysis Methods 0.000 claims description 24
• 125000006239 protecting group Chemical group 0.000 claims description 20
• 125000004076 pyridyl group Chemical group 0.000 claims description 18
• 229910052736 halogen Inorganic materials 0.000 claims description 15
• 150000002367 halogens Chemical class 0.000 claims description 15
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
• 229910052731 fluorine Inorganic materials 0.000 claims description 13
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
• 239000002253 acid Substances 0.000 claims description 11
• 239000011737 fluorine Substances 0.000 claims description 11
• 229910052801 chlorine Inorganic materials 0.000 claims description 10
• 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 claims description 9
• 230000015572 biosynthetic process Effects 0.000 claims description 9
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
• 239000004480 active ingredient Substances 0.000 claims description 6
• 230000005526 G1 to G0 transition Effects 0.000 claims description 5
• 229910052794 bromium Inorganic materials 0.000 claims description 5
• 230000008569 process Effects 0.000 claims description 5
• XHKJBNCTUYFLDC-UHFFFAOYSA-N 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoic acid Chemical compound C1=NC(N)=CC=C1CC(C(O)=O)C1=CN(C2CCCCC2)C=N1 XHKJBNCTUYFLDC-UHFFFAOYSA-N 0.000 claims description 4
• IQZKZQSOVLMDRA-UHFFFAOYSA-N 3-(6-aminopyridin-3-yl)-2-(1-cyclopentylimidazol-4-yl)propanoic acid Chemical compound C1=NC(N)=CC=C1CC(C(O)=O)C1=CN(C2CCCC2)C=N1 IQZKZQSOVLMDRA-UHFFFAOYSA-N 0.000 claims description 4
• 230000002378 acidificating effect Effects 0.000 claims description 4
• 239000003814 drug Substances 0.000 claims description 4
• 229910052740 iodine Inorganic materials 0.000 claims description 4
• 238000000926 separation method Methods 0.000 claims description 4
• 125000001425 triazolyl group Chemical group 0.000 claims description 4
• WJBQXBVLVFMKCZ-UHFFFAOYSA-N 2-hydroxyethyl 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoate Chemical compound C1=NC(N)=CC=C1CC(C(=O)OCCO)C1=CN(C2CCCCC2)C=N1 WJBQXBVLVFMKCZ-UHFFFAOYSA-N 0.000 claims description 3
• 239000000654 additive Substances 0.000 claims description 3
• 238000001212 derivatisation Methods 0.000 claims description 3
• IRLIYIPUIDRSIO-UHFFFAOYSA-N methyl 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoate Chemical compound C=1N(C2CCCCC2)C=NC=1C(C(=O)OC)CC1=CC=C(N)N=C1 IRLIYIPUIDRSIO-UHFFFAOYSA-N 0.000 claims description 3
• 238000002360 preparation method Methods 0.000 claims description 3
• WEGXHKRQVOAGFJ-UHFFFAOYSA-N 3-(6-aminopyridin-3-yl)-2-[1-(4,4-dimethylcyclohexyl)imidazol-4-yl]propanoic acid Chemical compound C1CC(C)(C)CCC1N1C=C(C(CC=2C=NC(N)=CC=2)C(O)=O)N=C1 WEGXHKRQVOAGFJ-UHFFFAOYSA-N 0.000 claims description 2
• MUHISURTDGVAGF-UHFFFAOYSA-N cyclopropylmethyl 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoate Chemical compound C1=NC(N)=CC=C1CC(C=1N=CN(C=1)C1CCCCC1)C(=O)OCC1CC1 MUHISURTDGVAGF-UHFFFAOYSA-N 0.000 claims description 2
• WIQPBDWLVQXSNI-UHFFFAOYSA-N propan-2-yl 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoate Chemical compound C=1N(C2CCCCC2)C=NC=1C(C(=O)OC(C)C)CC1=CC=C(N)N=C1 WIQPBDWLVQXSNI-UHFFFAOYSA-N 0.000 claims description 2
• 230000000996 additive effect Effects 0.000 claims 1
• 239000004615 ingredient Substances 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
• 239000000243 solution Substances 0.000 description 96
• 125000000217 alkyl group Chemical group 0.000 description 64
• 238000005160 1H NMR spectroscopy Methods 0.000 description 53
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 41
• 125000003118 aryl group Chemical group 0.000 description 38
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 36
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
• 239000000741 silica gel Substances 0.000 description 31
• 229910002027 silica gel Inorganic materials 0.000 description 31
• 235000002639 sodium chloride Nutrition 0.000 description 31
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
• 230000002829 reductive effect Effects 0.000 description 26
• 239000012071 phase Substances 0.000 description 25
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 24
• 229910052757 nitrogen Inorganic materials 0.000 description 23
• 239000011734 sodium Substances 0.000 description 23
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
• 238000006243 chemical reaction Methods 0.000 description 22
• 125000004433 nitrogen atom Chemical group N* 0.000 description 22
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 239000002904 solvent Substances 0.000 description 18
• 229920006395 saturated elastomer Polymers 0.000 description 17
• 239000007787 solid Substances 0.000 description 17
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 16
• 239000012074 organic phase Substances 0.000 description 16
• 238000000746 purification Methods 0.000 description 16
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
• 125000006413 ring segment Chemical group 0.000 description 15
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 14
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
• 239000011541 reaction mixture Substances 0.000 description 12
• 208000007536 Thrombosis Diseases 0.000 description 11
• 239000000047 product Substances 0.000 description 11
• 229910000104 sodium hydride Inorganic materials 0.000 description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• 125000004432 carbon atom Chemical group C* 0.000 description 10
• WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 10
• 238000003756 stirring Methods 0.000 description 10
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 238000005194 fractionation Methods 0.000 description 9
• 238000002953 preparative HPLC Methods 0.000 description 9
• 239000012312 sodium hydride Substances 0.000 description 9
• 238000011282 treatment Methods 0.000 description 9
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• 238000001816 cooling Methods 0.000 description 8
• 239000000284 extract Substances 0.000 description 8
• WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 7
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
• 239000012442 inert solvent Substances 0.000 description 7
• 238000004519 manufacturing process Methods 0.000 description 7
• 235000019260 propionic acid Nutrition 0.000 description 7
• POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 6
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
• BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 6
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
• 108090000190 Thrombin Proteins 0.000 description 6
• 235000001014 amino acid Nutrition 0.000 description 6
• 150000001413 amino acids Chemical class 0.000 description 6
• 125000003277 amino group Chemical group 0.000 description 6
• ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 6
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 6
• QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
• 125000005842 heteroatom Chemical class 0.000 description 6
• 150000002430 hydrocarbons Chemical group 0.000 description 6
• XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 6
• 229960004072 thrombin Drugs 0.000 description 6
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 5
• 102000009123 Fibrin Human genes 0.000 description 5
• 108010073385 Fibrin Proteins 0.000 description 5
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
• 125000004419 alkynylene group Chemical group 0.000 description 5
• 125000004122 cyclic group Chemical group 0.000 description 5
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
• 229950003499 fibrin Drugs 0.000 description 5
• 230000023597 hemostasis Effects 0.000 description 5
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
• 229910052760 oxygen Inorganic materials 0.000 description 5
• 239000001301 oxygen Substances 0.000 description 5
• 125000000714 pyrimidinyl group Chemical group 0.000 description 5
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 5
• 239000000126 substance Substances 0.000 description 5
• JKBGHFXEMZZLFY-UHFFFAOYSA-N tert-butyl n-[5-(bromomethyl)pyridin-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(CBr)C=N1 JKBGHFXEMZZLFY-UHFFFAOYSA-N 0.000 description 5
• LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 4
• CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 4
• CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 4
• OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 4
• ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical compound C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 description 4
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
• VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 4
• RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 4
• MSRJJSCOWHWGGX-UHFFFAOYSA-N 2h-1,3-diazepine Chemical compound C1N=CC=CC=N1 MSRJJSCOWHWGGX-UHFFFAOYSA-N 0.000 description 4
• GUUULVAMQJLDSY-UHFFFAOYSA-N 4,5-dihydro-1,2-thiazole Chemical compound C1CC=NS1 GUUULVAMQJLDSY-UHFFFAOYSA-N 0.000 description 4
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
• 108090000790 Enzymes Proteins 0.000 description 4
• 102000004190 Enzymes Human genes 0.000 description 4
• WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 4
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
• 239000004472 Lysine Substances 0.000 description 4
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 4
• 125000003342 alkenyl group Chemical group 0.000 description 4
• XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 4
• 238000004440 column chromatography Methods 0.000 description 4
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
• 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 4
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
• PPSZHCXTGRHULJ-UHFFFAOYSA-N dioxazine Chemical compound O1ON=CC=C1 PPSZHCXTGRHULJ-UHFFFAOYSA-N 0.000 description 4
• 201000010099 disease Diseases 0.000 description 4
• 229940088598 enzyme Drugs 0.000 description 4
• 230000020764 fibrinolysis Effects 0.000 description 4
• 239000000706 filtrate Substances 0.000 description 4
• MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 4
• JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
• IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 4
• 239000002244 precipitate Substances 0.000 description 4
• 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 4
• USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 4
• DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 4
• PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 4
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
• ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 4
• 229910052717 sulfur Inorganic materials 0.000 description 4
• 239000011593 sulfur Substances 0.000 description 4
• 238000001356 surgical procedure Methods 0.000 description 4
• 238000003786 synthesis reaction Methods 0.000 description 4
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 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
• JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 3
• FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 3
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 3
• JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 3
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