CA2260190A1 - New amidino derivatives and their use as thrombin inhibitors - Google Patents
New amidino derivatives and their use as thrombin inhibitors Download PDFInfo
- Publication number
- CA2260190A1 CA2260190A1 CA002260190A CA2260190A CA2260190A1 CA 2260190 A1 CA2260190 A1 CA 2260190A1 CA 002260190 A CA002260190 A CA 002260190A CA 2260190 A CA2260190 A CA 2260190A CA 2260190 A1 CA2260190 A1 CA 2260190A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- aminoiminomethylphenyl
- ethoxy
- compound
- phenyl
- 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.)
- Abandoned
Links
- 229940122388 Thrombin inhibitor Drugs 0.000 title description 10
- 239000003868 thrombin inhibitor Substances 0.000 title description 10
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 309
- 229960004072 thrombin Drugs 0.000 claims abstract description 34
- 108090000190 Thrombin Proteins 0.000 claims abstract description 30
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 230000005764 inhibitory process Effects 0.000 claims abstract description 13
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 12
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 7
- 229940127219 anticoagulant drug Drugs 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 88
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 71
- -1 C(O)OR6 Chemical group 0.000 claims description 49
- 238000006243 chemical reaction Methods 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 39
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 239000012634 fragment Substances 0.000 claims description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 26
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 22
- 125000004494 ethyl ester group Chemical group 0.000 claims description 22
- 230000008569 process Effects 0.000 claims description 19
- MNURPFVONZPVLA-UHFFFAOYSA-N 2-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1Cl MNURPFVONZPVLA-UHFFFAOYSA-N 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 229910020008 S(O) Inorganic materials 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 9
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 9
- 210000004369 blood Anatomy 0.000 claims description 8
- 239000008280 blood Substances 0.000 claims description 8
- 125000001475 halogen functional group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- 201000005665 thrombophilia Diseases 0.000 claims description 6
- HIULNHONUJTOTQ-UHFFFAOYSA-N 2-chloro-4-fluorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(F)C=C1Cl HIULNHONUJTOTQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- JKWKDCLQRIYOKA-UHFFFAOYSA-N 2-[n-(benzenesulfonyl)-3-[2-(4-methanehydrazonoylphenyl)ethoxy]anilino]acetic acid Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(N(CC(O)=O)S(=O)(=O)C=2C=CC=CC=2)=C1 JKWKDCLQRIYOKA-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004955 1,4-cyclohexylene group Chemical group [H]C1([H])C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])C1([H])[*:2] 0.000 claims description 2
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 2
- PKBBVTXFSHDWFE-UHFFFAOYSA-N 2,5-dibromo-n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCSC1=CC=CC=C1NS(=O)(=O)C1=CC(Br)=CC=C1Br PKBBVTXFSHDWFE-UHFFFAOYSA-N 0.000 claims description 2
- SFODECRGFXKZTD-UHFFFAOYSA-N 2-chloro-n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylphenyl]benzenesulfonamide Chemical compound C=1C(OCCC=2C=CC(C=NN)=CC=2)=CC(C)=CC=1NS(=O)(=O)C1=CC=CC=C1Cl SFODECRGFXKZTD-UHFFFAOYSA-N 0.000 claims description 2
- SODNDLJETLIHHH-UHFFFAOYSA-N 3-bromo-n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCSC1=CC=CC=C1NS(=O)(=O)C1=CC=CC(Br)=C1 SODNDLJETLIHHH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- BNJGKIKKLFZHCC-UHFFFAOYSA-N n-(2-chlorophenyl)sulfonyl-2-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylanilino]acetamide Chemical compound C=1C(OCCC=2C=CC(C=NN)=CC=2)=CC(C)=CC=1NCC(=O)NS(=O)(=O)C1=CC=CC=C1Cl BNJGKIKKLFZHCC-UHFFFAOYSA-N 0.000 claims description 2
- JUQZCOUERXMZDM-UHFFFAOYSA-N n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCSC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=C1 JUQZCOUERXMZDM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 4
- ZOANUIGMJGECCT-UHFFFAOYSA-N 2-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylanilino]propanoic acid Chemical compound C=1C=CC=C(Cl)C=1S(=O)(=O)N(C(C)C(O)=O)C(C=1)=CC(C)=CC=1OCCC1=CC=C(C=NN)C=C1 ZOANUIGMJGECCT-UHFFFAOYSA-N 0.000 claims 3
- SXYIRMGNMOHKTP-UHFFFAOYSA-N 2-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylanilino]acetic acid Chemical compound C=1C(N(CC(O)=O)S(=O)(=O)C=2C(=CC=CC=2)Cl)=CC(C)=CC=1OCCC1=CC=C(C=NN)C=C1 SXYIRMGNMOHKTP-UHFFFAOYSA-N 0.000 claims 2
- KZXXBGHWTCMNRO-UHFFFAOYSA-N 3-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylanilino]butanoic acid Chemical compound C=1C=CC=C(Cl)C=1S(=O)(=O)N(C(CC(O)=O)C)C(C=1)=CC(C)=CC=1OCCC1=CC=C(C=NN)C=C1 KZXXBGHWTCMNRO-UHFFFAOYSA-N 0.000 claims 2
- RIOVAEMMVQGMIB-UHFFFAOYSA-N 4-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylanilino]pentanoic acid Chemical compound C=1C=CC=C(Cl)C=1S(=O)(=O)N(C(CCC(O)=O)C)C(C=1)=CC(C)=CC=1OCCC1=CC=C(C=NN)C=C1 RIOVAEMMVQGMIB-UHFFFAOYSA-N 0.000 claims 2
- PXFLZLNBSUZGEO-UHFFFAOYSA-N 5-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylanilino]hexanoic acid Chemical compound C=1C=CC=C(Cl)C=1S(=O)(=O)N(C(CCCC(O)=O)C)C(C=1)=CC(C)=CC=1OCCC1=CC=C(C=NN)C=C1 PXFLZLNBSUZGEO-UHFFFAOYSA-N 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 2
- VIYPBXWLXCOTCK-UHFFFAOYSA-N 2,4,5-trichloro-n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCSC1=CC=CC=C1NS(=O)(=O)C1=CC(Cl)=C(Cl)C=C1Cl VIYPBXWLXCOTCK-UHFFFAOYSA-N 0.000 claims 1
- DCBXKBOKMOUHLK-UHFFFAOYSA-N 2,5-dichloro-n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCSC1=CC=CC=C1NS(=O)(=O)C1=CC(Cl)=CC=C1Cl DCBXKBOKMOUHLK-UHFFFAOYSA-N 0.000 claims 1
- IMUNGGYEMMRXSY-UHFFFAOYSA-N 2,5-dichloro-n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]thiophene-3-sulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(NS(=O)(=O)C2=C(SC(Cl)=C2)Cl)=C1 IMUNGGYEMMRXSY-UHFFFAOYSA-N 0.000 claims 1
- ROPUXMGHPVVTIF-UHFFFAOYSA-N 2-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylanilino]propanamide Chemical compound C=1C=CC=C(Cl)C=1S(=O)(=O)N(C(C)C(N)=O)C(C=1)=CC(C)=CC=1OCCC1=CC=C(C=NN)C=C1 ROPUXMGHPVVTIF-UHFFFAOYSA-N 0.000 claims 1
- KAEXKJWWYZBVQX-UHFFFAOYSA-N 2-chloro-4-fluoro-n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCSC1=CC=CC=C1NS(=O)(=O)C1=CC=C(F)C=C1Cl KAEXKJWWYZBVQX-UHFFFAOYSA-N 0.000 claims 1
- STJQNMHPYQBUGU-UHFFFAOYSA-N 2-chloro-n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]-5-methoxybenzenesulfonamide Chemical compound COC1=CC=C(Cl)C(S(=O)(=O)NC=2C(=CC=CC=2)SCCC=2C=CC(C=NN)=CC=2)=C1 STJQNMHPYQBUGU-UHFFFAOYSA-N 0.000 claims 1
- JJAFAAWADDIEHZ-UHFFFAOYSA-N 2-chloro-n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(NS(=O)(=O)C=2C(=CC=CC=2)Cl)=C1 JJAFAAWADDIEHZ-UHFFFAOYSA-N 0.000 claims 1
- ZDTGQOSIABKQFX-UHFFFAOYSA-N 2-cyano-n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(NS(=O)(=O)C=2C(=CC=CC=2)C#N)=C1 ZDTGQOSIABKQFX-UHFFFAOYSA-N 0.000 claims 1
- ZNQQZJCWFWWUQY-UHFFFAOYSA-N 2-fluoro-n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(NS(=O)(=O)C=2C(=CC=CC=2)F)=C1 ZNQQZJCWFWWUQY-UHFFFAOYSA-N 0.000 claims 1
- VKHVVVQVGFDCJW-UHFFFAOYSA-N 3,4-dibromo-n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCSC1=CC=CC=C1NS(=O)(=O)C1=CC=C(Br)C(Br)=C1 VKHVVVQVGFDCJW-UHFFFAOYSA-N 0.000 claims 1
- FFKVFRHTHWVIQK-UHFFFAOYSA-N 3-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylanilino]butanamide Chemical compound C=1C=CC=C(Cl)C=1S(=O)(=O)N(C(CC(N)=O)C)C(C=1)=CC(C)=CC=1OCCC1=CC=C(C=NN)C=C1 FFKVFRHTHWVIQK-UHFFFAOYSA-N 0.000 claims 1
- AQBALOXWAKCVGC-UHFFFAOYSA-N 4-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylanilino]pentanamide Chemical compound C=1C=CC=C(Cl)C=1S(=O)(=O)N(C(CCC(N)=O)C)C(C=1)=CC(C)=CC=1OCCC1=CC=C(C=NN)C=C1 AQBALOXWAKCVGC-UHFFFAOYSA-N 0.000 claims 1
- ZZJKRCJENKBNOA-UHFFFAOYSA-N 4-fluoro-n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(NS(=O)(=O)C=2C=CC(F)=CC=2)=C1 ZZJKRCJENKBNOA-UHFFFAOYSA-N 0.000 claims 1
- IBJLVYOMOBJPAF-UHFFFAOYSA-N 5-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylanilino]pentanamide Chemical compound C=1C(N(CCCCC(N)=O)S(=O)(=O)C=2C(=CC=CC=2)Cl)=CC(C)=CC=1OCCC1=CC=C(C=NN)C=C1 IBJLVYOMOBJPAF-UHFFFAOYSA-N 0.000 claims 1
- HPZGISYRJBTKDM-UHFFFAOYSA-N 5-bromo-n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]-2-methoxybenzenesulfonamide Chemical compound COC1=CC=C(Br)C=C1S(=O)(=O)NC1=CC=CC=C1SCCC1=CC=C(C=NN)C=C1 HPZGISYRJBTKDM-UHFFFAOYSA-N 0.000 claims 1
- FAJATWKXQOVACU-UHFFFAOYSA-N 5-chloro-n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]thiophene-2-sulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(NS(=O)(=O)C=2SC(Cl)=CC=2)=C1 FAJATWKXQOVACU-UHFFFAOYSA-N 0.000 claims 1
- 101100173726 Arabidopsis thaliana OR23 gene Proteins 0.000 claims 1
- HIGODVUIJZCVIB-UHFFFAOYSA-N NN=CC1=CC=C(C=C1)CCSC1=C(C=CC=C1)NS(=O)(=O)C1=C(C(=CC(=C1C)C)C)C Chemical compound NN=CC1=CC=C(C=C1)CCSC1=C(C=CC=C1)NS(=O)(=O)C1=C(C(=CC(=C1C)C)C)C HIGODVUIJZCVIB-UHFFFAOYSA-N 0.000 claims 1
- JYNZIOFUHBJABQ-UHFFFAOYSA-N allyl-{6-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-hexyl-}-methyl-amin Chemical compound C=1OC2=CC(OCCCCCCN(C)CC=C)=CC=C2C=1C1=CC=C(Br)C=C1 JYNZIOFUHBJABQ-UHFFFAOYSA-N 0.000 claims 1
- ZKAMSFVASSJCON-UHFFFAOYSA-N n-(2-hydroxyethyl)-n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(N(CCO)S(=O)(=O)C=2C=CC=CC=2)=C1 ZKAMSFVASSJCON-UHFFFAOYSA-N 0.000 claims 1
- FSFYAJPVOMBDGK-UHFFFAOYSA-N n-(benzenesulfonyl)-1-dimethylphosphoryl-n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]formamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(C(=O)P(C)(=O)C)C(C=1)=CC=CC=1OCCC1=CC=C(C=NN)C=C1 FSFYAJPVOMBDGK-UHFFFAOYSA-N 0.000 claims 1
- FTSASJXRLLORTF-UHFFFAOYSA-N n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]-2-methoxy-5-methylbenzenesulfonamide Chemical compound COC1=CC=C(C)C=C1S(=O)(=O)NC1=CC=CC=C1SCCC1=CC=C(C=NN)C=C1 FTSASJXRLLORTF-UHFFFAOYSA-N 0.000 claims 1
- XRISKDXCJKJFJY-UHFFFAOYSA-N n-[2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]-3,4-dimethoxybenzenesulfonamide Chemical compound C1=C(OC)C(OC)=CC=C1S(=O)(=O)NC1=CC=CC=C1SCCC1=CC=C(C=NN)C=C1 XRISKDXCJKJFJY-UHFFFAOYSA-N 0.000 claims 1
- TZYFIHILTWFVFO-UHFFFAOYSA-N n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]-2-methylphenyl]benzenesulfonamide Chemical compound C1=CC=C(OCCC=2C=CC(C=NN)=CC=2)C(C)=C1NS(=O)(=O)C1=CC=CC=C1 TZYFIHILTWFVFO-UHFFFAOYSA-N 0.000 claims 1
- VLNVAOIFEQCTIB-UHFFFAOYSA-N n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylphenyl]benzenesulfonamide Chemical compound C=1C(OCCC=2C=CC(C=NN)=CC=2)=CC(C)=CC=1NS(=O)(=O)C1=CC=CC=C1 VLNVAOIFEQCTIB-UHFFFAOYSA-N 0.000 claims 1
- PIZUIFDXAUNTOJ-UHFFFAOYSA-N n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]-1-phenylmethanesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(NS(=O)(=O)CC=2C=CC=CC=2)=C1 PIZUIFDXAUNTOJ-UHFFFAOYSA-N 0.000 claims 1
- LSTIKTUDDORGRM-UHFFFAOYSA-N n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]-2,5-dimethylbenzenesulfonamide Chemical compound CC1=CC=C(C)C(S(=O)(=O)NC=2C=C(OCCC=3C=CC(C=NN)=CC=3)C=CC=2)=C1 LSTIKTUDDORGRM-UHFFFAOYSA-N 0.000 claims 1
- CVCARYSTFHWYIA-UHFFFAOYSA-N n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]-2-(trifluoromethoxy)benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(NS(=O)(=O)C=2C(=CC=CC=2)OC(F)(F)F)=C1 CVCARYSTFHWYIA-UHFFFAOYSA-N 0.000 claims 1
- AKQQLSUXNFQFOS-UHFFFAOYSA-N n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]-3,5-dimethyl-1,2-oxazole-4-sulfonamide Chemical compound CC1=NOC(C)=C1S(=O)(=O)NC1=CC=CC(OCCC=2C=CC(C=NN)=CC=2)=C1 AKQQLSUXNFQFOS-UHFFFAOYSA-N 0.000 claims 1
- BNYREDCQRBWCNQ-UHFFFAOYSA-N n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]-3-methyl-2h-imidazole-1-sulfonamide Chemical compound C1=CN(C)CN1S(=O)(=O)NC1=CC=CC(OCCC=2C=CC(C=NN)=CC=2)=C1 BNYREDCQRBWCNQ-UHFFFAOYSA-N 0.000 claims 1
- QMLSYOLBVAUPHO-UHFFFAOYSA-N n-[3-[2-(4-methanehydrazonoylphenyl)ethoxy]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCOC1=CC=CC(NS(=O)(=O)C=2C=CC=CC=2)=C1 QMLSYOLBVAUPHO-UHFFFAOYSA-N 0.000 claims 1
- DJPQYCDMGLZKKF-UHFFFAOYSA-N n-[3-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NN)=CC=C1CCSC1=CC=CC(NS(=O)(=O)C=2C=CC=CC=2)=C1 DJPQYCDMGLZKKF-UHFFFAOYSA-N 0.000 claims 1
- HJNWVQKSKQPACN-UHFFFAOYSA-N n-[5-[2-(4-methanehydrazonoylphenyl)ethoxy]-2-methylphenyl]benzenesulfonamide Chemical compound C1=C(NS(=O)(=O)C=2C=CC=CC=2)C(C)=CC=C1OCCC1=CC=C(C=NN)C=C1 HJNWVQKSKQPACN-UHFFFAOYSA-N 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 21
- 230000002860 competitive effect Effects 0.000 abstract description 4
- 102100027612 Kallikrein-11 Human genes 0.000 abstract 1
- 101710152431 Trypsin-like protease Proteins 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 98
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 95
- 238000005481 NMR spectroscopy Methods 0.000 description 82
- 239000002904 solvent Substances 0.000 description 75
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 71
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 68
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 67
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 67
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 60
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 58
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
- 239000000243 solution Substances 0.000 description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
- 229910004373 HOAc Inorganic materials 0.000 description 49
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 47
- 235000019439 ethyl acetate Nutrition 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 229910001868 water Inorganic materials 0.000 description 44
- 239000000203 mixture Substances 0.000 description 32
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 238000001704 evaporation Methods 0.000 description 29
- 230000008020 evaporation Effects 0.000 description 29
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- 238000003818 flash chromatography Methods 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000000377 silicon dioxide Substances 0.000 description 24
- 238000000746 purification Methods 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 229910052681 coesite Inorganic materials 0.000 description 21
- 229910052906 cristobalite Inorganic materials 0.000 description 21
- 235000012239 silicon dioxide Nutrition 0.000 description 21
- 229910052682 stishovite Inorganic materials 0.000 description 21
- 229910052905 tridymite Inorganic materials 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 19
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 238000002953 preparative HPLC Methods 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 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 14
- 239000012267 brine Substances 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- WNVVRCKTQSCPAC-UHFFFAOYSA-N 2,4,5-trichlorobenzenesulfonyl chloride Chemical compound ClC1=CC(Cl)=C(S(Cl)(=O)=O)C=C1Cl WNVVRCKTQSCPAC-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 10
- 101150041968 CDC13 gene Proteins 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- NQAYCMBZPAARNO-UHFFFAOYSA-N 2-cyanobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1C#N NQAYCMBZPAARNO-UHFFFAOYSA-N 0.000 description 8
- RBSJBNYPTGMZIH-UHFFFAOYSA-N 4-(2-hydroxyethyl)benzonitrile Chemical compound OCCC1=CC=C(C#N)C=C1 RBSJBNYPTGMZIH-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 241000282414 Homo sapiens Species 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
- 238000001914 filtration Methods 0.000 description 8
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 235000015320 potassium carbonate Nutrition 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 229940124530 sulfonamide Drugs 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 206010053567 Coagulopathies Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000035602 clotting Effects 0.000 description 6
- 230000015271 coagulation Effects 0.000 description 6
- 238000005345 coagulation Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000011321 prophylaxis Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000012047 saturated solution Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- KMVZDSQHLDGKGV-UHFFFAOYSA-N 2-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=CC=C1S(Cl)(=O)=O KMVZDSQHLDGKGV-UHFFFAOYSA-N 0.000 description 5
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 5
- 235000019260 propionic acid Nutrition 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 108010073385 Fibrin Proteins 0.000 description 4
- 102000009123 Fibrin Human genes 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000002399 angioplasty Methods 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 4
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 4
- 229950003499 fibrin Drugs 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- HPZGABMELSCHDK-UHFFFAOYSA-N n-[3-[2-(4-cyanophenyl)ethoxy]phenyl]benzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)NC(C=1)=CC=CC=1OCCC1=CC=C(C#N)C=C1 HPZGABMELSCHDK-UHFFFAOYSA-N 0.000 description 4
- OIPPWFOQEKKFEE-UHFFFAOYSA-N orcinol Chemical compound CC1=CC(O)=CC(O)=C1 OIPPWFOQEKKFEE-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000001151 peptidyl group Chemical group 0.000 description 4
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 125000003944 tolyl group Chemical group 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- INOXVJVSLFPKIQ-UHFFFAOYSA-N 2-chloro-3-[3-[2-(4-cyanophenyl)ethoxy]-5-methylphenyl]benzenesulfonamide Chemical compound C=1C(C=2C(=C(C=CC=2)S(N)(=O)=O)Cl)=CC(C)=CC=1OCCC1=CC=C(C#N)C=C1 INOXVJVSLFPKIQ-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- 208000001435 Thromboembolism Diseases 0.000 description 3
- 239000003875 Wang resin Substances 0.000 description 3
- NERFNHBZJXXFGY-UHFFFAOYSA-N [4-[(4-methylphenyl)methoxy]phenyl]methanol Chemical compound C1=CC(C)=CC=C1COC1=CC=C(CO)C=C1 NERFNHBZJXXFGY-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003593 chromogenic compound Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 150000003456 sulfonamides Chemical class 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229960003766 thrombin (human) Drugs 0.000 description 3
- 108010036927 trypsin-like serine protease Proteins 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- 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 2
- HZKGRCIKQBHSNA-KCQAQPDRSA-N (3s,4r,6r)-4-bromo-10-chloro-5,5,9-trimethyl-1-methylidenespiro[5.5]undec-9-en-3-ol Chemical compound C1CC(C)=C(Cl)C[C@@]21C(C)(C)[C@@H](Br)[C@@H](O)CC2=C HZKGRCIKQBHSNA-KCQAQPDRSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- QLWKZLVKTHCBEW-UHFFFAOYSA-N 2-[2-(4-methanehydrazonoylphenyl)ethylsulfanyl]aniline Chemical compound C1=CC(C=NN)=CC=C1CCSC1=CC=CC=C1N QLWKZLVKTHCBEW-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
- WXVLHEDZALZOSU-UHFFFAOYSA-N 4-[2-(2-aminophenyl)sulfanylethyl]benzonitrile Chemical compound NC1=CC=CC=C1SCCC1=CC=C(C#N)C=C1 WXVLHEDZALZOSU-UHFFFAOYSA-N 0.000 description 2
- OBUSRLOJMTZPJC-UHFFFAOYSA-N 4-[2-(3-amino-2-methylphenoxy)ethyl]benzonitrile Chemical compound CC1=C(N)C=CC=C1OCCC1=CC=C(C#N)C=C1 OBUSRLOJMTZPJC-UHFFFAOYSA-N 0.000 description 2
- BZVINBMELLBWPJ-UHFFFAOYSA-N 4-[2-(3-amino-5-methylphenoxy)ethyl]benzonitrile Chemical compound CC1=CC(N)=CC(OCCC=2C=CC(=CC=2)C#N)=C1 BZVINBMELLBWPJ-UHFFFAOYSA-N 0.000 description 2
- WYTCGJWZRTZGFU-UHFFFAOYSA-N 4-[2-(3-nitrophenoxy)ethyl]benzonitrile Chemical compound [O-][N+](=O)C1=CC=CC(OCCC=2C=CC(=CC=2)C#N)=C1 WYTCGJWZRTZGFU-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- FQVLOBQILLZLJA-UHFFFAOYSA-N 5-chlorobenzene-1,3-diol Chemical compound OC1=CC(O)=CC(Cl)=C1 FQVLOBQILLZLJA-UHFFFAOYSA-N 0.000 description 2
- 108010058207 Anistreplase Proteins 0.000 description 2
- 206010003178 Arterial thrombosis Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 108010094028 Prothrombin Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 102000002262 Thromboplastin Human genes 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N Valeric acid Natural products CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- 150000005224 alkoxybenzenes Chemical class 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 2
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- OLFGZVIWCIMPLI-UHFFFAOYSA-N tert-butyl n-[[5-amino-2-[2-(3-aminophenoxy)ethyl]phenyl]methylidene]carbamate Chemical compound CC(C)(C)OC(=O)N=CC1=CC(N)=CC=C1CCOC1=CC=CC(N)=C1 OLFGZVIWCIMPLI-UHFFFAOYSA-N 0.000 description 2
- 230000002537 thrombolytic effect Effects 0.000 description 2
- OGNVQLDIPUXYDH-ZPKKHLQPSA-N (2R,3R,4S)-3-(2-methylpropanoylamino)-4-(4-phenyltriazol-1-yl)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid Chemical compound CC(C)C(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(O)=O)=C[C@@H]1N1N=NC(C=2C=CC=CC=2)=C1 OGNVQLDIPUXYDH-ZPKKHLQPSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical group [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- YJKHOUIVWKQRSL-UHFFFAOYSA-N 1-(3,5-dimethoxyphenyl)ethanone Chemical compound COC1=CC(OC)=CC(C(C)=O)=C1 YJKHOUIVWKQRSL-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- WQHNWJBSROXROL-UHFFFAOYSA-N 1-chloro-3,5-dimethoxybenzene Chemical compound COC1=CC(Cl)=CC(OC)=C1 WQHNWJBSROXROL-UHFFFAOYSA-N 0.000 description 1
- CDQDCHVJLUPXEF-UHFFFAOYSA-N 1-ethyl-3,5-dimethoxybenzene Chemical compound CCC1=CC(OC)=CC(OC)=C1 CDQDCHVJLUPXEF-UHFFFAOYSA-N 0.000 description 1
- KXUGUWTUFUWYRS-UHFFFAOYSA-N 1-methylimidazole-4-sulfonyl chloride Chemical compound CN1C=NC(S(Cl)(=O)=O)=C1 KXUGUWTUFUWYRS-UHFFFAOYSA-N 0.000 description 1
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- ZCXRROBIIMQMHR-UHFFFAOYSA-N 2,3,5,6-tetramethylbenzenesulfonyl chloride Chemical compound CC1=CC(C)=C(C)C(S(Cl)(=O)=O)=C1C ZCXRROBIIMQMHR-UHFFFAOYSA-N 0.000 description 1
- ZLMPLIWURYRGEB-UHFFFAOYSA-N 2,5-dibromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC(Br)=CC=C1Br ZLMPLIWURYRGEB-UHFFFAOYSA-N 0.000 description 1
- BXCOSWRSIISQSL-UHFFFAOYSA-N 2,5-dichlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(Cl)C(S(Cl)(=O)=O)=C1 BXCOSWRSIISQSL-UHFFFAOYSA-N 0.000 description 1
- FZVZUIBYLZZOEW-UHFFFAOYSA-N 2,5-dimethylbenzenesulfonyl chloride Chemical compound CC1=CC=C(C)C(S(Cl)(=O)=O)=C1 FZVZUIBYLZZOEW-UHFFFAOYSA-N 0.000 description 1
- MVIRKWKVTSPBQQ-UHFFFAOYSA-N 2-(4-cyanophenyl)ethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC1=CC=C(C#N)C=C1 MVIRKWKVTSPBQQ-UHFFFAOYSA-N 0.000 description 1
- BLGQROIGCHBMQP-UHFFFAOYSA-N 2-(aminomethyl)benzenecarboximidamide Chemical class NCC1=CC=CC=C1C(N)=N BLGQROIGCHBMQP-UHFFFAOYSA-N 0.000 description 1
- XWKAVQKJQBISOL-UHFFFAOYSA-N 2-(phenylazaniumyl)propanoate Chemical compound OC(=O)C(C)NC1=CC=CC=C1 XWKAVQKJQBISOL-UHFFFAOYSA-N 0.000 description 1
- QDPTWQREHYIBCZ-UHFFFAOYSA-N 2-[(2-chlorophenyl)sulfonylamino]-2-[3-[2-(4-cyanophenyl)ethoxy]phenyl]acetic acid Chemical compound C=1C=CC(OCCC=2C=CC(=CC=2)C#N)=CC=1C(C(=O)O)NS(=O)(=O)C1=CC=CC=C1Cl QDPTWQREHYIBCZ-UHFFFAOYSA-N 0.000 description 1
- WKRIAWJVQUSLSJ-UHFFFAOYSA-N 2-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-cyanophenyl)ethoxy]-5-methylanilino]propanoic acid Chemical compound C=1C=CC=C(Cl)C=1S(=O)(=O)N(C(C)C(O)=O)C(C=1)=CC(C)=CC=1OCCC1=CC=C(C#N)C=C1 WKRIAWJVQUSLSJ-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 1
- FCFPJKHVCHKCMP-UHFFFAOYSA-N 2-chloro-4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C(Cl)=C1 FCFPJKHVCHKCMP-UHFFFAOYSA-N 0.000 description 1
- MEAYPBQBXNTXBT-UHFFFAOYSA-N 2-chloro-5-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(Cl)C(S(Cl)(=O)=O)=C1 MEAYPBQBXNTXBT-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- ZSZKAQCISWFDCQ-UHFFFAOYSA-N 2-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC=C1S(Cl)(=O)=O ZSZKAQCISWFDCQ-UHFFFAOYSA-N 0.000 description 1
- BJYNYQGJTZULJI-UHFFFAOYSA-N 2-methoxy-5-methylbenzenesulfonyl chloride Chemical compound COC1=CC=C(C)C=C1S(Cl)(=O)=O BJYNYQGJTZULJI-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- PBCQAUMKUSTMJD-UHFFFAOYSA-N 3,4-dibromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C(Br)=C1 PBCQAUMKUSTMJD-UHFFFAOYSA-N 0.000 description 1
- RSJSYCZYQNJQPY-UHFFFAOYSA-N 3,4-dimethoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(S(Cl)(=O)=O)C=C1OC RSJSYCZYQNJQPY-UHFFFAOYSA-N 0.000 description 1
- GZLPFEYTAAXJCP-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole-4-sulfonyl chloride Chemical compound CC1=NOC(C)=C1S(Cl)(=O)=O GZLPFEYTAAXJCP-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- ULRWVBOTHBJGDX-UHFFFAOYSA-N 3-[2-(4-methanehydrazonoylphenyl)ethoxy]-5-methylphenol Chemical compound CC1=CC(O)=CC(OCCC=2C=CC(C=NN)=CC=2)=C1 ULRWVBOTHBJGDX-UHFFFAOYSA-N 0.000 description 1
- NCUABBHFJSFKOJ-UHFFFAOYSA-N 3-amino-5-methylphenol Chemical compound CC1=CC(N)=CC(O)=C1 NCUABBHFJSFKOJ-UHFFFAOYSA-N 0.000 description 1
- KFFUEVDMVNIOHA-UHFFFAOYSA-N 3-aminobenzenethiol Chemical compound NC1=CC=CC(S)=C1 KFFUEVDMVNIOHA-UHFFFAOYSA-N 0.000 description 1
- PJGOLCXVWIYXRQ-UHFFFAOYSA-N 3-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC(Br)=C1 PJGOLCXVWIYXRQ-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- PRZFAGGNAKJNQW-UHFFFAOYSA-N 3-methyl-1,2-benzothiazol-5-amine Chemical compound C1=C(N)C=C2C(C)=NSC2=C1 PRZFAGGNAKJNQW-UHFFFAOYSA-N 0.000 description 1
- RTZZCYNQPHTPPL-UHFFFAOYSA-N 3-nitrophenol Chemical compound OC1=CC=CC([N+]([O-])=O)=C1 RTZZCYNQPHTPPL-UHFFFAOYSA-N 0.000 description 1
- PBGDGOWGZQNAHJ-UHFFFAOYSA-N 4-(aminomethyl)piperidine-1-carboximidamide Chemical compound NCC1CCN(C(N)=N)CC1 PBGDGOWGZQNAHJ-UHFFFAOYSA-N 0.000 description 1
- JIRFFPCGOFYARB-UHFFFAOYSA-N 4-[2-(3-amino-4-methylphenoxy)ethyl]benzonitrile Chemical compound C1=C(N)C(C)=CC=C1OCCC1=CC=C(C#N)C=C1 JIRFFPCGOFYARB-UHFFFAOYSA-N 0.000 description 1
- YJCILSAVOPYSRB-UHFFFAOYSA-N 4-[2-(3-aminophenoxy)ethyl]benzonitrile Chemical compound NC1=CC=CC(OCCC=2C=CC(=CC=2)C#N)=C1 YJCILSAVOPYSRB-UHFFFAOYSA-N 0.000 description 1
- RJTDFIGYKWCHCN-UHFFFAOYSA-N 4-[2-(3-aminophenyl)sulfanylethyl]benzonitrile Chemical compound NC1=CC=CC(SCCC=2C=CC(=CC=2)C#N)=C1 RJTDFIGYKWCHCN-UHFFFAOYSA-N 0.000 description 1
- VWTSZWULMTZKMK-UHFFFAOYSA-N 4-[2-(3-chloro-5-hydroxyphenoxy)ethyl]benzonitrile Chemical compound OC1=CC(Cl)=CC(OCCC=2C=CC(=CC=2)C#N)=C1 VWTSZWULMTZKMK-UHFFFAOYSA-N 0.000 description 1
- JSWIHQYACRJBJY-UHFFFAOYSA-N 4-[2-(3-ethyl-5-hydroxyphenoxy)ethyl]benzonitrile Chemical compound CCC1=CC(O)=CC(OCCC=2C=CC(=CC=2)C#N)=C1 JSWIHQYACRJBJY-UHFFFAOYSA-N 0.000 description 1
- CHBQHWWIPSWCMD-UHFFFAOYSA-N 4-[2-(3-hydroxy-5-methylphenoxy)ethyl]benzonitrile Chemical compound CC1=CC(O)=CC(OCCC=2C=CC(=CC=2)C#N)=C1 CHBQHWWIPSWCMD-UHFFFAOYSA-N 0.000 description 1
- LTJWQIVYQKIMBP-UHFFFAOYSA-N 4-[2-(4-methyl-3-nitrophenoxy)ethyl]benzonitrile Chemical compound C1=C([N+]([O-])=O)C(C)=CC=C1OCCC1=CC=C(C#N)C=C1 LTJWQIVYQKIMBP-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- AYTJJFGJOPPBGB-UHFFFAOYSA-N 4-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-cyanophenyl)ethoxy]-5-methylanilino]pentanoic acid Chemical compound C=1C=CC=C(Cl)C=1S(=O)(=O)N(C(CCC(O)=O)C)C(C=1)=CC(C)=CC=1OCCC1=CC=C(C#N)C=C1 AYTJJFGJOPPBGB-UHFFFAOYSA-N 0.000 description 1
- KJMONDCRPSGATH-UHFFFAOYSA-N 4-[n-(2-chlorophenyl)sulfonyl-3-[2-(4-hydrazinylidene-2-methylcyclohexa-1,5-dien-1-yl)ethoxy]-5-methylanilino]pentanoic acid Chemical compound C=1C=CC=C(Cl)C=1S(=O)(=O)N(C(CCC(O)=O)C)C(C=1)=CC(C)=CC=1OCCC1=C(C)CC(=NN)C=C1 KJMONDCRPSGATH-UHFFFAOYSA-N 0.000 description 1
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-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
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 description 1
- BQEXDUKMTVYBRK-UHFFFAOYSA-N 4-methyl-3-nitrophenol Chemical compound CC1=CC=C(O)C=C1[N+]([O-])=O BQEXDUKMTVYBRK-UHFFFAOYSA-N 0.000 description 1
- IXSBNNRUQYYMRM-UHFFFAOYSA-N 5-bromo-2-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(Br)C=C1S(Cl)(=O)=O IXSBNNRUQYYMRM-UHFFFAOYSA-N 0.000 description 1
- SORSTNOXGOXWAO-UHFFFAOYSA-N 5-chlorothiophene-2-sulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)S1 SORSTNOXGOXWAO-UHFFFAOYSA-N 0.000 description 1
- AKIIGQKHZHPDDW-UHFFFAOYSA-N 5-chlorothiophene-3-sulfonyl chloride Chemical compound ClC1=CC(S(Cl)(=O)=O)=CS1 AKIIGQKHZHPDDW-UHFFFAOYSA-N 0.000 description 1
- MSFGJICDOLGZQK-UHFFFAOYSA-N 5-ethylbenzene-1,3-diol Chemical compound CCC1=CC(O)=CC(O)=C1 MSFGJICDOLGZQK-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010056867 Activated protein C resistance Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 102000004411 Antithrombin III Human genes 0.000 description 1
- 108090000935 Antithrombin III Proteins 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000021910 Cerebral Arterial disease Diseases 0.000 description 1
- RLZWTUCSEUFDSO-UHFFFAOYSA-N ClC1=C(C=CC=C1)S(=O)(=O)N(C(CCC(=O)O)C)C1=CC(=CC(=C1)C)OCCC1=C(C=C(C=C1)OCC)C=N Chemical compound ClC1=C(C=CC=C1)S(=O)(=O)N(C(CCC(=O)O)C)C1=CC(=CC(=C1)C)OCCC1=C(C=C(C=C1)OCC)C=N RLZWTUCSEUFDSO-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 108010014172 Factor V Proteins 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 108010071289 Factor XIII Proteins 0.000 description 1
- 102000004032 Heparin Cofactor II Human genes 0.000 description 1
- 108090000481 Heparin Cofactor II Proteins 0.000 description 1
- 206010062506 Heparin-induced thrombocytopenia Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 238000000023 Kugelrohr distillation Methods 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000004221 Multiple Trauma Diseases 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- NPKSPKHJBVJUKB-UHFFFAOYSA-N N-phenylglycine Chemical compound OC(=O)CNC1=CC=CC=C1 NPKSPKHJBVJUKB-UHFFFAOYSA-N 0.000 description 1
- IIGSQUGLMKAFMY-UHFFFAOYSA-N NC1=CC(=C(C=C1)CCOC=1C=C(C=C(C1)C)O)C=NO Chemical compound NC1=CC(=C(C=C1)CCOC=1C=C(C=C(C1)C)O)C=NO IIGSQUGLMKAFMY-UHFFFAOYSA-N 0.000 description 1
- HJOPKHLGMXGSDY-UHFFFAOYSA-N NC1=CC(=C(C=C1)CCOC=1C=C(C=CC1)N(S(=O)(=O)C1=CC=CC=C1)CCO)C=NO Chemical compound NC1=CC(=C(C=C1)CCOC=1C=C(C=CC1)N(S(=O)(=O)C1=CC=CC=C1)CCO)C=NO HJOPKHLGMXGSDY-UHFFFAOYSA-N 0.000 description 1
- FMPIVGRSUQJESL-UHFFFAOYSA-N NC=1C(=C(C=CC1)O)C.OC=1C(=C(C=CC1)NC(OC(C)(C)C)=O)C Chemical compound NC=1C(=C(C=CC1)O)C.OC=1C(=C(C=CC1)NC(OC(C)(C)C)=O)C FMPIVGRSUQJESL-UHFFFAOYSA-N 0.000 description 1
- YGFWVKYMNVDEBM-UHFFFAOYSA-N NC=1C=C(C=CC1)O.C(C)(C)(C)OC(NC1=CC(=CC=C1)O)=O Chemical compound NC=1C=C(C=CC1)O.C(C)(C)(C)OC(NC1=CC(=CC=C1)O)=O YGFWVKYMNVDEBM-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- GLUYKHMBGKQBHE-JYJNAYRXSA-N Phe-Val-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 GLUYKHMBGKQBHE-JYJNAYRXSA-N 0.000 description 1
- 108010001014 Plasminogen Activators Proteins 0.000 description 1
- 102000001938 Plasminogen Activators Human genes 0.000 description 1
- 241001237728 Precis Species 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 102000017975 Protein C Human genes 0.000 description 1
- 229940096437 Protein S Drugs 0.000 description 1
- 102000029301 Protein S Human genes 0.000 description 1
- 108010066124 Protein S Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 102000007466 Purinergic P2 Receptors Human genes 0.000 description 1
- 108010085249 Purinergic P2 Receptors Proteins 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 102000003938 Thromboxane Receptors Human genes 0.000 description 1
- 108090000300 Thromboxane Receptors Proteins 0.000 description 1
- 108010069102 Thromboxane-A synthase Proteins 0.000 description 1
- 229910010062 TiCl3 Inorganic materials 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- KXHUFHLUXSEUCC-UHFFFAOYSA-N [3-(hydroxymethoxy)phenoxy]methanol Chemical compound OCOC1=CC=CC(OCO)=C1 KXHUFHLUXSEUCC-UHFFFAOYSA-N 0.000 description 1
- QSWKBRYUGFWUAZ-UHFFFAOYSA-N [3-chloro-5-[2-(4-cyanophenyl)ethoxy]phenyl] 2-chloro-4-fluorobenzenesulfonate Chemical compound ClC1=CC(F)=CC=C1S(=O)(=O)OC1=CC(Cl)=CC(OCCC=2C=CC(=CC=2)C#N)=C1 QSWKBRYUGFWUAZ-UHFFFAOYSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 150000001642 boronic acid derivatives Chemical group 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 206010061592 cardiac fibrillation Diseases 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 238000013130 cardiovascular surgery Methods 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- VACOMSNNWGXHSF-UHFFFAOYSA-N chloro(dimethylphosphoryl)methane Chemical compound CP(C)(=O)CCl VACOMSNNWGXHSF-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 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 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000004802 cyanophenyl group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- OJWDCWZSMJBOBR-UHFFFAOYSA-N ethyl 2-[3-[2-(4-cyanophenyl)ethoxy]-5-methylanilino]acetate Chemical compound CCOC(=O)CNC1=CC(C)=CC(OCCC=2C=CC(=CC=2)C#N)=C1 OJWDCWZSMJBOBR-UHFFFAOYSA-N 0.000 description 1
- FMFDWCAQDWISCD-UHFFFAOYSA-N ethyl 2-anilinopropanoate Chemical compound CCOC(=O)C(C)NC1=CC=CC=C1 FMFDWCAQDWISCD-UHFFFAOYSA-N 0.000 description 1
- OPXQLUFLTHEZST-UHFFFAOYSA-N ethyl 3-bromobutanoate Chemical compound CCOC(=O)CC(C)Br OPXQLUFLTHEZST-UHFFFAOYSA-N 0.000 description 1
- CTVCPHLFHPQRNF-UHFFFAOYSA-N ethyl 4-bromopentanoate Chemical compound CCOC(=O)CCC(C)Br CTVCPHLFHPQRNF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 108010091897 factor V Leiden Proteins 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 229940012444 factor xiii Drugs 0.000 description 1
- 230000002600 fibrillogenic effect Effects 0.000 description 1
- 108010069898 fibrinogen fragment X Proteins 0.000 description 1
- 239000002319 fibrinogen receptor antagonist Substances 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000001261 hydroxy acids Chemical class 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002406 microsurgery Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- WXDSYHPXVSJKHH-UHFFFAOYSA-N n-[3-[2-(4-cyanophenyl)ethoxy]-5-methylphenyl]benzenesulfonamide Chemical compound C=1C(OCCC=2C=CC(=CC=2)C#N)=CC(C)=CC=1NS(=O)(=O)C1=CC=CC=C1 WXDSYHPXVSJKHH-UHFFFAOYSA-N 0.000 description 1
- AKFVSEBMPWRGQL-UHFFFAOYSA-N n-[3-[2-(4-cyanophenyl)ethoxy]phenyl]-n-(2-hydroxyethyl)benzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(CCO)C(C=1)=CC=CC=1OCCC1=CC=C(C#N)C=C1 AKFVSEBMPWRGQL-UHFFFAOYSA-N 0.000 description 1
- DPNQSQMSPILQTN-UHFFFAOYSA-N n-[3-[2-(4-cyanophenyl)ethylsulfanyl]phenyl]benzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)NC(C=1)=CC=CC=1SCCC1=CC=C(C#N)C=C1 DPNQSQMSPILQTN-UHFFFAOYSA-N 0.000 description 1
- YARGAWXPAXCHLJ-UHFFFAOYSA-N n-[3-[2-[4-(ethoxyiminomethyl)phenyl]ethoxy]phenyl]benzenesulfonamide Chemical compound C1=CC(C=NOCC)=CC=C1CCOC1=CC=CC(NS(=O)(=O)C=2C=CC=CC=2)=C1 YARGAWXPAXCHLJ-UHFFFAOYSA-N 0.000 description 1
- OEEALMPGOZYWAB-UHFFFAOYSA-N n-[5-[2-[4-(ethoxyiminomethyl)phenyl]ethoxy]-2-methylphenyl]benzenesulfonamide Chemical compound C1=CC(C=NOCC)=CC=C1CCOC1=CC=C(C)C(NS(=O)(=O)C=2C=CC=CC=2)=C1 OEEALMPGOZYWAB-UHFFFAOYSA-N 0.000 description 1
- MACKTSOEPQOALR-UHFFFAOYSA-N n-ethoxy-1-[4-[2-(3-nitrophenoxy)ethyl]phenyl]methanimine Chemical compound C1=CC(C=NOCC)=CC=C1CCOC1=CC=CC([N+]([O-])=O)=C1 MACKTSOEPQOALR-UHFFFAOYSA-N 0.000 description 1
- QZJOPRMVLCPTRX-UHFFFAOYSA-N n-{3-[2-(4-cyanophenyl)ethoxy]phenyl}-n-(dimethyloxophosphinyl-methyl)-benzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(C(C)(C)P(=O)=O)C(C=1)=CC=CC=1OCCC1=CC=C(C#N)C=C1 QZJOPRMVLCPTRX-UHFFFAOYSA-N 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940037201 oris Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- WYMSBXTXOHUIGT-UHFFFAOYSA-N paraoxon Chemical compound CCOP(=O)(OCC)OC1=CC=C([N+]([O-])=O)C=C1 WYMSBXTXOHUIGT-UHFFFAOYSA-N 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 description 1
- OAHKWDDSKCRNFE-UHFFFAOYSA-N phenylmethanesulfonyl chloride Chemical compound ClS(=O)(=O)CC1=CC=CC=C1 OAHKWDDSKCRNFE-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- RGCLLPNLLBQHPF-HJWRWDBZSA-N phosphamidon Chemical compound CCN(CC)C(=O)C(\Cl)=C(/C)OP(=O)(OC)OC RGCLLPNLLBQHPF-HJWRWDBZSA-N 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 229940127126 plasminogen activator Drugs 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- LETVJWLLIMJADE-UHFFFAOYSA-N pyridazin-3-amine Chemical class NC1=CC=CN=N1 LETVJWLLIMJADE-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 108010073863 saruplase Proteins 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- PTXONJABBSUNFT-UHFFFAOYSA-N tert-butyl n-(3-hydroxy-2-methylphenyl)carbamate Chemical compound CC1=C(O)C=CC=C1NC(=O)OC(C)(C)C PTXONJABBSUNFT-UHFFFAOYSA-N 0.000 description 1
- URNOARJOTIWYAO-UHFFFAOYSA-N tert-butyl n-(3-hydroxy-5-methylphenyl)carbamate Chemical compound CC1=CC(O)=CC(NC(=O)OC(C)(C)C)=C1 URNOARJOTIWYAO-UHFFFAOYSA-N 0.000 description 1
- GLLODZAQYRKNAL-UHFFFAOYSA-N tert-butyl n-[3-[2-(4-cyanophenyl)ethoxy]-5-methylphenyl]carbamate Chemical compound CC1=CC(NC(=O)OC(C)(C)C)=CC(OCCC=2C=CC(=CC=2)C#N)=C1 GLLODZAQYRKNAL-UHFFFAOYSA-N 0.000 description 1
- WKHQYZBZPWFNBL-UHFFFAOYSA-N tert-butyl n-[3-[2-(4-cyanophenyl)ethoxy]phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(OCCC=2C=CC(=CC=2)C#N)=C1 WKHQYZBZPWFNBL-UHFFFAOYSA-N 0.000 description 1
- ZEYNALXLBIWPGZ-UHFFFAOYSA-N tert-butyl n-[[5-amino-2-[2-(3-hydroxy-5-methylphenoxy)ethyl]phenyl]methylidene]carbamate Chemical compound CC1=CC(O)=CC(OCCC=2C(=CC(N)=CC=2)C=NC(=O)OC(C)(C)C)=C1 ZEYNALXLBIWPGZ-UHFFFAOYSA-N 0.000 description 1
- LVHWYKJPDJJASJ-UHFFFAOYSA-N tert-butyl n-[[5-amino-2-[2-(3-nitrophenoxy)ethyl]phenyl]methylidene]carbamate Chemical compound CC(C)(C)OC(=O)N=CC1=CC(N)=CC=C1CCOC1=CC=CC([N+]([O-])=O)=C1 LVHWYKJPDJJASJ-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/71—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
- C07D261/16—Benzene-sulfonamido isoxazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5304—Acyclic saturated phosphine oxides or thioxides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9602646-3 | 1996-07-04 | ||
| SE9602646A SE9602646D0 (sv) | 1996-07-04 | 1996-07-04 | Pharmaceutically-useful compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2260190A1 true CA2260190A1 (en) | 1998-01-15 |
Family
ID=20403276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002260190A Abandoned CA2260190A1 (en) | 1996-07-04 | 1997-06-26 | New amidino derivatives and their use as thrombin inhibitors |
Country Status (24)
| Country | Link |
|---|---|
| US (2) | US6221898B1 (enExample) |
| EP (1) | EP0917528B1 (enExample) |
| JP (1) | JP2000515505A (enExample) |
| KR (1) | KR20000022437A (enExample) |
| CN (1) | CN1228765A (enExample) |
| AR (1) | AR007614A1 (enExample) |
| AT (1) | ATE224365T1 (enExample) |
| BR (1) | BR9710142A (enExample) |
| CA (1) | CA2260190A1 (enExample) |
| CZ (1) | CZ1299A3 (enExample) |
| DE (1) | DE69715635T2 (enExample) |
| EE (1) | EE9900006A (enExample) |
| HU (1) | HUP9902410A3 (enExample) |
| ID (1) | ID19479A (enExample) |
| IL (1) | IL127885A0 (enExample) |
| IS (1) | IS4930A (enExample) |
| NO (1) | NO986180L (enExample) |
| NZ (1) | NZ333394A (enExample) |
| PL (1) | PL331047A1 (enExample) |
| SE (1) | SE9602646D0 (enExample) |
| SK (1) | SK172098A3 (enExample) |
| TR (1) | TR199802767T2 (enExample) |
| WO (1) | WO1998001422A1 (enExample) |
| ZA (1) | ZA975591B (enExample) |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9602646D0 (sv) | 1996-07-04 | 1996-07-04 | Astra Ab | Pharmaceutically-useful compounds |
| TW499412B (en) | 1996-11-26 | 2002-08-21 | Dimensional Pharm Inc | Aminoguanidines and alkoxyguanidines as protease inhibitors |
| AR013084A1 (es) | 1997-06-19 | 2000-12-13 | Astrazeneca Ab | Derivados de amidino utiles como inhibidores de la trombina, composicion farmaceutica, utilizacion de dichos compuestos para la preparacion demedicamentos y proceso para la preparacion de los compuestos mencionados |
| SE9704543D0 (sv) | 1997-12-05 | 1997-12-05 | Astra Ab | New compounds |
| AR023510A1 (es) | 1999-04-21 | 2002-09-04 | Astrazeneca Ab | Un equipo de partes, formulacion farmaceutica y uso de un inhibidor de trombina. |
| US6548706B2 (en) | 1999-12-23 | 2003-04-15 | Aerojet Fine Chemicals Llc | Preparation of 2S,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl) -p-nitrobenzenesulfonylamide hydrochloride and other derivatives of 2-hydroxy-1,3-diamines |
| EP2314563A3 (en) * | 1999-12-23 | 2012-04-04 | Ampac Fine Chemicals LLC | Improved preparation of 2S,3S-N-isobutyl-N-(2-hydroxy-3-amino-4-phenylbutyl)-p-nitrobenzenesulfonylamide hydrochloride and other derivatives of 2-hydroxy-1,3-diamines |
| PL206094B1 (pl) * | 2000-10-04 | 2010-06-30 | Kissei Pharmaceutical | Pochodne 5-amidyno-2- hydroksybenzenosulfonamidu, zawierająca je kompozycja farmaceutyczna oraz zastosowanie takiej pochodnej |
| US7129233B2 (en) * | 2000-12-01 | 2006-10-31 | Astrazeneca Ab | Mandelic acid derivatives and their use as thrombin inhibitors |
| 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 |
| US7067539B2 (en) | 2001-02-08 | 2006-06-27 | Schering Corporation | Cannabinoid receptor ligands |
| US7507767B2 (en) | 2001-02-08 | 2009-03-24 | Schering Corporation | Cannabinoid receptor ligands |
| AR034517A1 (es) * | 2001-06-21 | 2004-02-25 | Astrazeneca Ab | Formulacion farmaceutica |
| EP1312602A1 (en) * | 2001-11-15 | 2003-05-21 | Eisai Co., Ltd. | Amidino derivatives, and anticoagulants and thrombosis therapeutic agents containing them |
| JP4209659B2 (ja) | 2001-11-15 | 2009-01-14 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | アミジノ誘導体並びにそれを用いた抗血液凝固剤および血栓症治療剤 |
| KR100966705B1 (ko) * | 2001-12-20 | 2010-06-29 | 브리스톨-마이어스 스큅 컴퍼니 | β-아밀로이드 저해제로서의α-(Ν-술폰아미도)아세트아미드 유도체 |
| SE0201659D0 (sv) * | 2002-05-31 | 2002-05-31 | Astrazeneca Ab | Modified release pharmaceutical formulation |
| SE0201661D0 (sv) * | 2002-05-31 | 2002-05-31 | Astrazeneca Ab | New salts |
| US20050026168A1 (en) * | 2002-12-13 | 2005-02-03 | Genesis Group Inc. | Method for the detection of risk factors associated with myocardial infarction |
| US7781424B2 (en) * | 2003-05-27 | 2010-08-24 | Astrazeneca Ab | Modified release pharmaceutical formulation |
| US7524354B2 (en) * | 2005-07-07 | 2009-04-28 | Research Foundation Of State University Of New York | Controlled synthesis of highly monodispersed gold nanoparticles |
| TW200827336A (en) * | 2006-12-06 | 2008-07-01 | Astrazeneca Ab | New crystalline forms |
| US20090061000A1 (en) * | 2007-08-31 | 2009-03-05 | Astrazeneca Ab | Pharmaceutical formulation use 030 |
| RU2481329C2 (ru) * | 2008-06-23 | 2013-05-10 | Астеллас Фарма Инк. | Сульфонамидные соединения или их соли |
| GB0815784D0 (en) | 2008-08-29 | 2008-10-08 | Xention Ltd | Novel potassium channel blockers |
| GB0815782D0 (en) | 2008-08-29 | 2008-10-08 | Xention Ltd | Novel potassium channel blockers |
| GB0815781D0 (en) | 2008-08-29 | 2008-10-08 | Xention Ltd | Novel potassium channel blockers |
| CA2822039C (en) | 2010-12-16 | 2019-05-28 | Allergan, Inc. | Sulfur derivatives as chemokine receptor modulators |
| CN102358753B (zh) * | 2011-10-14 | 2013-06-05 | 山西大学 | 一种胰蛋白酶抑制剂活性片段衍生物及其制备方法和应用 |
| CN115803318A (zh) * | 2020-05-20 | 2023-03-14 | 拜耳公司 | 制备(5s)-5-({2-[4-(丁氧羰基)苯基]乙基}[2-(2-{[3-氯-4’-(三氟甲基)[联苯]-4-基]甲氧基}苯基)乙基]氨基)-5,6,7,8-四氢喹啉-2-甲酸丁酯的方法 |
Family Cites Families (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU178398B (en) | 1979-06-12 | 1982-04-28 | Gyogyszerkutato Intezet | Process for producing new agmatine derivatives of activity against haemagglutination |
| HU192646B (en) | 1984-12-21 | 1987-06-29 | Gyogyszerkutato Intezet | Process for preparing new n-alkyl-peptide aldehydes |
| AU600226B2 (en) | 1985-02-04 | 1990-08-09 | Merrell Pharmaceuticals Inc. | Novel peptidase inhibitors |
| US5187157A (en) | 1987-06-05 | 1993-02-16 | Du Pont Merck Pharmaceutical Company | Peptide boronic acid inhibitors of trypsin-like proteases |
| EP0362002B1 (en) | 1988-09-01 | 1995-07-26 | Merrell Dow Pharmaceuticals Inc. | HIV protease inhibitors |
| ZA897515B (en) | 1988-10-07 | 1990-06-27 | Merrell Dow Pharma | Novel peptidase inhibitors |
| TW201303B (enExample) | 1990-07-05 | 1993-03-01 | Hoffmann La Roche | |
| CA2075154A1 (en) | 1991-08-06 | 1993-02-07 | Neelakantan Balasubramanian | Peptide aldehydes as antithrombotic agents |
| SE9102462D0 (sv) | 1991-08-28 | 1991-08-28 | Astra Ab | New isosteric peptides |
| CZ333492A3 (en) | 1991-11-12 | 1993-09-15 | Lilly Co Eli | Dipeptide of l-azetidine-2-carboxylic acids and l-argininaldehyde, process of its preparation and pharmaceutical preparation in which said dipeptide is comprised |
| SE9103612D0 (sv) | 1991-12-04 | 1991-12-04 | Astra Ab | New peptide derivatives |
| US5264457A (en) * | 1992-02-14 | 1993-11-23 | G. D. Searle & Co. | Phenyl amidines sulfonamides useful as platelet aggregation inhibitors |
| DE69314478T2 (de) | 1992-03-04 | 1999-02-11 | Gyogyszerkutato Intezet Kft., Budapest | Neuartige antikoagulierende peptidderivate und arzneimittel die solche enthalten so wie entsprechendes herstellungsverfahren |
| TW223629B (enExample) | 1992-03-06 | 1994-05-11 | Hoffmann La Roche | |
| US5583146A (en) | 1992-12-02 | 1996-12-10 | Bristol-Myers Squibb Company | Heterocyclic thrombin inhibitors |
| AU675981B2 (en) | 1992-12-02 | 1997-02-27 | Bristol-Myers Squibb Company | Guanidinyl-substituted heterocyclic thrombin inhibitors |
| TW257757B (enExample) * | 1993-03-03 | 1995-09-21 | Boehringer Mannheim Gmbh | |
| JPH06340619A (ja) | 1993-05-03 | 1994-12-13 | Bristol Myers Squibb Co | グアニジニルまたはアミジニル置換メチルアミノ複素環トロンビン抑制剤 |
| SE9301916D0 (sv) | 1993-06-03 | 1993-06-03 | Ab Astra | New peptides derivatives |
| US5780631A (en) | 1993-06-03 | 1998-07-14 | Astra Aktiebolag | Starting materials in the synthesis of thrombin and kininogenase inhibitors |
| EP0648780A1 (en) | 1993-08-26 | 1995-04-19 | Bristol-Myers Squibb Company | Heterocyclic thrombin inhibitors |
| TW394760B (en) | 1993-09-07 | 2000-06-21 | Hoffmann La Roche | Novel Carboxamides, process for their preparation and pharmaceutical composition containing the same |
| AU1025795A (en) | 1994-01-27 | 1995-08-03 | Mitsubishi Chemical Corporation | Prolineamide derivatives |
| US5705487A (en) | 1994-03-04 | 1998-01-06 | Eli Lilly And Company | Antithrombotic agents |
| IL112795A (en) | 1994-03-04 | 2001-01-28 | Astrazeneca Ab | Peptide derivatives as antithrombic agents their preparation and pharmaceutical compositions containing them |
| US5707966A (en) | 1994-03-04 | 1998-01-13 | Eli Lilly And Company | Antithrombotic agents |
| US5726159A (en) | 1994-03-04 | 1998-03-10 | Eli Lilly And Company | Antithrombotic agents |
| US5561146A (en) | 1994-06-10 | 1996-10-01 | Bristol-Myers Squibb Company | Modified guanidino and amidino thrombin inhibitors |
| DE4421052A1 (de) | 1994-06-17 | 1995-12-21 | Basf Ag | Neue Thrombininhibitoren, ihre Herstellung und Verwendung |
| US5510369A (en) | 1994-07-22 | 1996-04-23 | Merck & Co., Inc. | Pyrrolidine thrombin inhibitors |
| DE4430757A1 (de) | 1994-08-30 | 1996-03-07 | Boehringer Mannheim Gmbh | Neue 4-Aminopyridazine, Verfahren zu ihrer Herstellung sowie diese Verbindungen enthaltende Arzneimittel |
| DE4430755A1 (de) | 1994-08-30 | 1996-03-07 | Boehringer Mannheim Gmbh | Neue Phosphanoxide, Verfahren zu ihrer Herstellung sowie diese Verbindungen enthaltende Arzneimittel |
| CA2206532C (en) * | 1994-12-02 | 2006-07-11 | Yamanouchi Pharmaceutical Co., Ltd. | Novel amidinonaphthyl derivative or salt thereof |
| CA2211109A1 (en) | 1995-02-17 | 1996-08-22 | Basf Aktiengesellschaft | Novel thrombin inhibitors |
| US5710130A (en) | 1995-02-27 | 1998-01-20 | Eli Lilly And Company | Antithrombotic agents |
| US5629324A (en) | 1995-04-10 | 1997-05-13 | Merck & Co., Inc. | Thrombin inhibitors |
| IL118007A0 (en) * | 1995-05-24 | 1996-08-04 | Du Pont Merck Pharma | Isoxazoline compounds pharmaceutical compositions containing them and their use |
| SA96170106A (ar) | 1995-07-06 | 2005-12-03 | أسترا أكتيبولاج | مشتقات حامض أميني جديدة |
| US5792769A (en) | 1995-09-29 | 1998-08-11 | 3-Dimensional Pharmaceuticals, Inc. | Guanidino protease inhibitors |
| BR9610876A (pt) | 1995-09-29 | 1999-07-13 | Dimensional Pharm Inc | Inibidores de protease de guanidino |
| TWI238827B (en) | 1995-12-21 | 2005-09-01 | Astrazeneca Ab | Prodrugs of thrombin inhibitors |
| WO1997024135A1 (en) | 1995-12-29 | 1997-07-10 | 3-Dimensional Pharmaceuticals, Inc. | Amidino protease inhibitors |
| WO1997047299A1 (en) | 1996-06-12 | 1997-12-18 | 3-Dimensional Pharmaceuticals, Inc. | Amidino and guanidino heterocyclic protease inhibitors |
| SE9602646D0 (sv) * | 1996-07-04 | 1996-07-04 | Astra Ab | Pharmaceutically-useful compounds |
| DE19632773A1 (de) | 1996-08-14 | 1998-02-19 | Basf Ag | Neue Thrombininhibitoren |
| DE19632772A1 (de) | 1996-08-14 | 1998-02-19 | Basf Ag | Neue Benzamidine |
| US6285302B1 (en) | 1998-12-28 | 2001-09-04 | Texas Instruments Incorporated | Runlength-limited code and method |
-
1996
- 1996-07-04 SE SE9602646A patent/SE9602646D0/xx unknown
-
1997
- 1997-06-23 AR ARP970102753A patent/AR007614A1/es not_active Application Discontinuation
- 1997-06-24 ZA ZA975591A patent/ZA975591B/xx unknown
- 1997-06-26 IL IL12788597A patent/IL127885A0/xx unknown
- 1997-06-26 DE DE69715635T patent/DE69715635T2/de not_active Expired - Fee Related
- 1997-06-26 AT AT97932085T patent/ATE224365T1/de not_active IP Right Cessation
- 1997-06-26 SK SK1720-98A patent/SK172098A3/sk unknown
- 1997-06-26 BR BR9710142A patent/BR9710142A/pt unknown
- 1997-06-26 US US08/894,833 patent/US6221898B1/en not_active Expired - Fee Related
- 1997-06-26 CA CA002260190A patent/CA2260190A1/en not_active Abandoned
- 1997-06-26 KR KR1019980710870A patent/KR20000022437A/ko not_active Withdrawn
- 1997-06-26 EE EEP199900006A patent/EE9900006A/xx unknown
- 1997-06-26 HU HU9902410A patent/HUP9902410A3/hu unknown
- 1997-06-26 TR TR1998/02767T patent/TR199802767T2/xx unknown
- 1997-06-26 JP JP10505123A patent/JP2000515505A/ja not_active Ceased
- 1997-06-26 NZ NZ333394A patent/NZ333394A/xx not_active IP Right Cessation
- 1997-06-26 CN CN97197578A patent/CN1228765A/zh active Pending
- 1997-06-26 CZ CZ9912A patent/CZ1299A3/cs unknown
- 1997-06-26 EP EP97932085A patent/EP0917528B1/en not_active Expired - Lifetime
- 1997-06-26 WO PCT/SE1997/001150 patent/WO1998001422A1/en not_active Ceased
- 1997-06-26 PL PL97331047A patent/PL331047A1/xx unknown
- 1997-07-02 ID IDP972305A patent/ID19479A/id unknown
-
1998
- 1998-12-21 IS IS4930A patent/IS4930A/is unknown
- 1998-12-29 NO NO986180A patent/NO986180L/no not_active Application Discontinuation
-
2001
- 2001-04-23 US US09/839,609 patent/US7074820B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| NO986180L (no) | 1999-03-04 |
| US7074820B2 (en) | 2006-07-11 |
| AU726236B2 (en) | 2000-11-02 |
| US6221898B1 (en) | 2001-04-24 |
| AR007614A1 (es) | 1999-11-10 |
| NZ333394A (en) | 2000-08-25 |
| JP2000515505A (ja) | 2000-11-21 |
| HUP9902410A3 (en) | 2001-10-29 |
| BR9710142A (pt) | 1999-08-10 |
| ID19479A (id) | 1998-07-16 |
| EP0917528B1 (en) | 2002-09-18 |
| WO1998001422A1 (en) | 1998-01-15 |
| KR20000022437A (ko) | 2000-04-25 |
| NO986180D0 (no) | 1998-12-29 |
| TR199802767T2 (xx) | 1999-04-21 |
| IL127885A0 (en) | 1999-10-28 |
| ATE224365T1 (de) | 2002-10-15 |
| EE9900006A (et) | 1999-06-15 |
| ZA975591B (en) | 1998-12-24 |
| SK172098A3 (en) | 1999-06-11 |
| US20020040043A1 (en) | 2002-04-04 |
| IS4930A (is) | 1998-12-21 |
| CN1228765A (zh) | 1999-09-15 |
| HUP9902410A2 (hu) | 1999-11-29 |
| AU3562897A (en) | 1998-02-02 |
| DE69715635D1 (de) | 2002-10-24 |
| PL331047A1 (en) | 1999-06-21 |
| CZ1299A3 (cs) | 1999-06-16 |
| SE9602646D0 (sv) | 1996-07-04 |
| EP0917528A1 (en) | 1999-05-26 |
| DE69715635T2 (de) | 2003-08-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0917528B1 (en) | New amidino derivatives and their use as thrombin inhibitors | |
| AU749555B2 (en) | Peptide-containing alpha-ketoamide cysteine and serine protease inhibitors | |
| US6576657B2 (en) | Amidino derivatives and their use as thrombin inhibitors | |
| EP0910573B1 (en) | New amino acid derivatives and their use as thrombin inhibitors | |
| US20070249578A1 (en) | New amidino derivatives and their use as thrombin inhibitors | |
| AU748834B2 (en) | New compounds | |
| WO2002026731A2 (en) | Quaternary amidino based inhibitors of factor xa | |
| AU726236C (en) | New amidino derivatives and their use as thrombin inhibitors | |
| EP1236712B1 (en) | Amidinophenylpyruvic acid derivative | |
| MXPA99000218A (es) | Nuevos derivados de amidino y su uso como inhibidores de trombina | |
| KR100483869B1 (ko) | 신규한 아미노산 유도체 및 트롬빈 억제제로서의 그의 용도 | |
| MXPA99011901A (en) | New amidino derivatives and their use as thrombin inhibitors | |
| CZ459299A3 (cs) | Nové amidinoderiváty a jejich použitíjako inhibitorů thrombinu | |
| MXPA00005483A (en) | New compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |