JP2010531352A5 - - Google Patents
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- JP2010531352A5 JP2010531352A5 JP2010514671A JP2010514671A JP2010531352A5 JP 2010531352 A5 JP2010531352 A5 JP 2010531352A5 JP 2010514671 A JP2010514671 A JP 2010514671A JP 2010514671 A JP2010514671 A JP 2010514671A JP 2010531352 A5 JP2010531352 A5 JP 2010531352A5
- Authority
- JP
- Japan
- Prior art keywords
- thrombin
- group
- hydrogen
- pharmaceutically acceptable
- alkyl group
- 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.)
- Pending
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- 150000001875 compounds Chemical class 0.000 claims description 54
- 108090000190 Thrombin Proteins 0.000 claims description 48
- 229960004072 thrombin Drugs 0.000 claims description 48
- 239000003868 thrombin inhibitor Substances 0.000 claims description 36
- 229940122388 Thrombin inhibitor Drugs 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 239000012453 solvate Substances 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 230000009424 thromboembolic effect Effects 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 230000001419 dependent effect Effects 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 description 23
- -1 aliphatic amino acids Chemical class 0.000 description 21
- 102000004169 proteins and genes Human genes 0.000 description 18
- 108090000623 proteins and genes Proteins 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000003446 ligand Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- 108010049003 Fibrinogen Proteins 0.000 description 9
- 102000008946 Fibrinogen Human genes 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 229940012952 fibrinogen Drugs 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 8
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 125000000539 amino acid group Chemical group 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- OIPPWFOQEKKFEE-UHFFFAOYSA-N orcinol Chemical compound CC1=CC(O)=CC(O)=C1 OIPPWFOQEKKFEE-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 5
- 229940092714 benzenesulfonic acid Drugs 0.000 description 5
- 239000003593 chromogenic compound Substances 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 238000003032 molecular docking Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- MNURPFVONZPVLA-UHFFFAOYSA-N 2-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1Cl MNURPFVONZPVLA-UHFFFAOYSA-N 0.000 description 4
- 0 Cc1cc(OS(c2c(*)cccc2)(=O)=O)cc(O*[n+](cc2)ccc2N)c1 Chemical compound Cc1cc(OS(c2c(*)cccc2)(=O)=O)cc(O*[n+](cc2)ccc2N)c1 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 102000009123 Fibrin Human genes 0.000 description 4
- 108010073385 Fibrin Proteins 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
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- 239000003814 drug Substances 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229920002521 macromolecule Polymers 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- JIFAWAXKXDTUHW-UHFFFAOYSA-N 2-fluorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1F JIFAWAXKXDTUHW-UHFFFAOYSA-N 0.000 description 3
- XGWZKPKLPOKIRV-UHFFFAOYSA-N 3-amino-n-methyl-4-(methylamino)-n-phenylbenzenesulfonamide Chemical compound C1=C(N)C(NC)=CC=C1S(=O)(=O)N(C)C1=CC=CC=C1 XGWZKPKLPOKIRV-UHFFFAOYSA-N 0.000 description 3
- SOGCFMBEGNGROL-UHFFFAOYSA-N 3-chloro-n-[2-(methylamino)-5-[methyl(phenyl)sulfamoyl]phenyl]propanamide Chemical compound C1=C(NC(=O)CCCl)C(NC)=CC=C1S(=O)(=O)N(C)C1=CC=CC=C1 SOGCFMBEGNGROL-UHFFFAOYSA-N 0.000 description 3
- SEWNAJIUKSTYOP-UHFFFAOYSA-N 4-chloro-3-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC(S(Cl)(=O)=O)=CC=C1Cl SEWNAJIUKSTYOP-UHFFFAOYSA-N 0.000 description 3
- 102000004411 Antithrombin III Human genes 0.000 description 3
- 108090000935 Antithrombin III Proteins 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003275 alpha amino acid group Chemical group 0.000 description 3
- 229960005348 antithrombin iii Drugs 0.000 description 3
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 3
- 229960003856 argatroban Drugs 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- VWKFKQZBGXBRPB-UHFFFAOYSA-N 2-[2-(4-aminopyridin-1-ium-1-yl)ethyl]-n,1-dimethyl-n-phenylbenzimidazole-5-sulfonamide;chloride Chemical compound [Cl-].C=1C=C2N(C)C(CC[N+]=3C=CC(N)=CC=3)=NC2=CC=1S(=O)(=O)N(C)C1=CC=CC=C1 VWKFKQZBGXBRPB-UHFFFAOYSA-N 0.000 description 2
- FLCUEXJOTNUYJB-UHFFFAOYSA-N 2-methoxycarbonylbenzenesulfonic acid Chemical compound COC(=O)C1=CC=CC=C1S(O)(=O)=O FLCUEXJOTNUYJB-UHFFFAOYSA-N 0.000 description 2
- WWMXDEJAUBGJGO-UHFFFAOYSA-N 3-(2-chloroethoxy)-5-methylphenol Chemical compound CC1=CC(O)=CC(OCCCl)=C1 WWMXDEJAUBGJGO-UHFFFAOYSA-N 0.000 description 2
- NDVKQVKMKNSXCD-UHFFFAOYSA-N 3-(3-chloropropoxy)-5-methylphenol Chemical compound CC1=CC(O)=CC(OCCCCl)=C1 NDVKQVKMKNSXCD-UHFFFAOYSA-N 0.000 description 2
- RECKGFUIHDPLLR-UHFFFAOYSA-N 3-(4-aminopyridin-1-ium-1-yl)-n-[2-(methylamino)-5-[methyl(phenyl)sulfamoyl]phenyl]propanamide;chloride Chemical compound [Cl-].CNC1=CC=C(S(=O)(=O)N(C)C=2C=CC=CC=2)C=C1NC(=O)CC[N+]1=CC=C(N)C=C1 RECKGFUIHDPLLR-UHFFFAOYSA-N 0.000 description 2
- WTGTWGLWOYWURD-UHFFFAOYSA-N 3-(4-chlorobutoxy)-5-methylphenol Chemical compound CC1=CC(O)=CC(OCCCCCl)=C1 WTGTWGLWOYWURD-UHFFFAOYSA-N 0.000 description 2
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 2
- ZRESUPFQMJFEHM-UHFFFAOYSA-N 4-chloro-n-methyl-3-nitro-n-phenylbenzenesulfonamide Chemical compound C=1C=C(Cl)C([N+]([O-])=O)=CC=1S(=O)(=O)N(C)C1=CC=CC=C1 ZRESUPFQMJFEHM-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241001272567 Hominoidea Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- KPKDBAHWPYDUQY-UHFFFAOYSA-N [3-(3-chloropropoxy)-5-methylphenyl] 2-chlorobenzenesulfonate Chemical compound CC1=CC(OCCCCl)=CC(OS(=O)(=O)C=2C(=CC=CC=2)Cl)=C1 KPKDBAHWPYDUQY-UHFFFAOYSA-N 0.000 description 2
- NVFZBJMKQROZIO-UHFFFAOYSA-N [3-(3-iodopropoxy)-5-methylphenyl] 2-chlorobenzenesulfonate Chemical compound CC1=CC(OCCCI)=CC(OS(=O)(=O)C=2C(=CC=CC=2)Cl)=C1 NVFZBJMKQROZIO-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
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- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000002429 anti-coagulating effect Effects 0.000 description 2
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- 239000004019 antithrombin Substances 0.000 description 2
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- 125000003636 chemical group Chemical group 0.000 description 2
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- 231100000636 lethal dose Toxicity 0.000 description 2
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- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- CJHLTSVWDWQALY-UHFFFAOYSA-N n-methyl-1-[4-(methylamino)-3-nitrophenyl]-1-oxo-n-phenylmethanesulfonamide Chemical compound C1=C([N+]([O-])=O)C(NC)=CC=C1C(=O)S(=O)(=O)N(C)C1=CC=CC=C1 CJHLTSVWDWQALY-UHFFFAOYSA-N 0.000 description 2
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- 238000004809 thin layer chromatography Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- RRRNQAKQPWWPKP-UHFFFAOYSA-N 1-(2-phenoxyethyl)pyridin-1-ium-4-amine;bromide Chemical compound [Br-].C1=CC(N)=CC=[N+]1CCOC1=CC=CC=C1 RRRNQAKQPWWPKP-UHFFFAOYSA-N 0.000 description 1
- USOOYIUDDIEITE-UHFFFAOYSA-N 1-(4-chloro-3-nitrophenyl)-n-methyl-1-oxo-n-phenylmethanesulfonamide Chemical compound C=1C=C(Cl)C([N+]([O-])=O)=CC=1C(=O)S(=O)(=O)N(C)C1=CC=CC=C1 USOOYIUDDIEITE-UHFFFAOYSA-N 0.000 description 1
- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- JXZZEXZZKAWDSP-UHFFFAOYSA-N 3-(2-(4-Benzamidopiperid-1-yl)ethyl)indole Chemical compound C1CN(CCC=2C3=CC=CC=C3NC=2)CCC1NC(=O)C1=CC=CC=C1 JXZZEXZZKAWDSP-UHFFFAOYSA-N 0.000 description 1
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| PCT/RU2008/000400 WO2009002228A2 (en) | 2007-06-28 | 2008-06-27 | New thrombin function compounds and pharmaceutical compositions based on them |
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| RU2353619C2 (ru) * | 2007-06-28 | 2009-04-27 | Общество С Ограниченной Ответственностью "Бионика" | Новые соединения, обладающие функцией антикоагулянтов, фармацевтические композиции на их основе для лечения тромботических состояний и плазмозамещающий раствор для коррекции гиперкоагуляционных нарушений при гемодилюции |
| WO2013048787A1 (en) | 2011-09-26 | 2013-04-04 | Yes, Inc. | Novel hemostatic compositions and dressings for bleeding |
| WO2013056116A1 (en) * | 2011-10-12 | 2013-04-18 | The Trustees Of Columbia University In The City Of New York | Hemostatic dressing for arterial bleeding |
| FR3030516B1 (fr) * | 2014-12-19 | 2019-12-27 | Galderma Research & Development | Derives sulfonamides bicycles en tant qu'agonistes inverses du recepteur gamma orphelin associe aux retinoides ror gamma (t) |
| RU2685261C1 (ru) * | 2018-04-05 | 2019-04-17 | Общество с ограниченной ответственностью "ФК ЛАБОРАТОРИЗ" | Вещество 4-амино-1-{ 2-[3-метил-5-(бензолсульфонилокси)фенокси] этил} -пиридиний хлорид, обладающее свойствами биологически активного агента, влияющими на естественно текущие процессы свертываемости крови млекопитающих, антикоагулянт на его основе и способ его получения путем химического синтеза |
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| US1469906A (en) | 1921-08-26 | 1923-10-09 | Augie L Hansen | Tufting needle |
| DE1245937B (enExample) * | 1964-09-09 | 1967-08-03 | ||
| US5089634A (en) * | 1984-08-20 | 1992-02-18 | Georgia Tech Research Corporation | Isocoumarins with cationic substituents |
| US5214052A (en) | 1987-07-28 | 1993-05-25 | Mitsubishi Kasei Corporation | Method for dissolving arginineamides and pharmaceutical compositions containing them |
| JPH0341065A (ja) * | 1989-07-06 | 1991-02-21 | Morishita Pharmaceut Co Ltd | アリールオキシアルキルイソチオウレア臭化水素酸塩類 |
| JP3084458B2 (ja) * | 1991-11-08 | 2000-09-04 | コニカ株式会社 | ハロゲン化銀写真感光材料 |
| TW257757B (enExample) * | 1993-03-03 | 1995-09-21 | Boehringer Mannheim Gmbh | |
| IL109319A0 (en) * | 1993-04-27 | 1994-07-31 | Du Pont Merck Pharma | Amidino and guanidino substituted boronic acid compounds |
| 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 |
| SE9404196D0 (sv) | 1994-12-02 | 1994-12-02 | Astra Ab | New antithrombotic formulation |
| US5792769A (en) * | 1995-09-29 | 1998-08-11 | 3-Dimensional Pharmaceuticals, Inc. | Guanidino protease inhibitors |
| ATE341317T1 (de) * | 1996-03-29 | 2006-10-15 | Ortho Mcneil Pharm Inc | Amidinohydrazone als protease-inhibitoren |
| AU725403B2 (en) * | 1996-09-13 | 2000-10-12 | Merck & Co., Inc. | Thrombin inhibitors |
| US5792799A (en) * | 1996-10-10 | 1998-08-11 | Athena Neurosciences, Inc. | Parenteral delivery of MAO A inhibitors |
| US5792779A (en) | 1997-02-19 | 1998-08-11 | Merck & Co., Inc. | Pyridinone thrombin inhibitors |
| US5886191A (en) * | 1997-08-18 | 1999-03-23 | Dupont Pharmaceuticals Company | Amidinoindoles, amidinoazoles, and analogs thereof |
| UA75093C2 (en) * | 2000-10-06 | 2006-03-15 | Dimensional Pharm Inc | Aminopyridinyl-,aminoguanidinyl-, and alkoxyguanidinesubstituted phenylsubstituted phenylacetamides as protease inhibitors |
| JP4896387B2 (ja) * | 2003-09-30 | 2012-03-14 | 武田薬品工業株式会社 | チアゾリン誘導体およびその用途 |
| AU2005229505B2 (en) * | 2004-03-02 | 2010-07-15 | F. Hoffmann-La Roche Ag | 4- (sulfanyl-pyrimidin-4-ylmethyl) -morpholine derivatives and related compounds as GABA receptor ligands for the treatment of anxiety, depression and epilepsy |
| CA2647597A1 (en) * | 2006-05-31 | 2007-12-06 | Abbott Laboratories | Thiazole compounds as cannabinoid receptor ligands and uses thereof |
| RU2353619C2 (ru) * | 2007-06-28 | 2009-04-27 | Общество С Ограниченной Ответственностью "Бионика" | Новые соединения, обладающие функцией антикоагулянтов, фармацевтические композиции на их основе для лечения тромботических состояний и плазмозамещающий раствор для коррекции гиперкоагуляционных нарушений при гемодилюции |
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2007
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2008
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- 2008-06-27 US US12/666,221 patent/US20100324058A1/en not_active Abandoned
- 2008-06-27 CA CA2693226A patent/CA2693226A1/en not_active Abandoned
- 2008-06-27 KR KR1020107002057A patent/KR20100039867A/ko not_active Ceased
- 2008-06-27 EP EP08794028A patent/EP2178838A2/en not_active Withdrawn
- 2008-06-27 CN CN200880104825A patent/CN101861304A/zh active Pending
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- 2008-06-27 EA EA201000063A patent/EA201000063A1/ru unknown
- 2008-06-27 WO PCT/RU2008/000400 patent/WO2009002228A2/en not_active Ceased
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