NO309984B1 - AnalogifremgangsmÕte for fremstilling av tripeptidantitrombotiske midler - Google Patents
AnalogifremgangsmÕte for fremstilling av tripeptidantitrombotiske midler Download PDFInfo
- Publication number
- NO309984B1 NO309984B1 NO913773A NO913773A NO309984B1 NO 309984 B1 NO309984 B1 NO 309984B1 NO 913773 A NO913773 A NO 913773A NO 913773 A NO913773 A NO 913773A NO 309984 B1 NO309984 B1 NO 309984B1
- Authority
- NO
- Norway
- Prior art keywords
- group
- formula
- boc
- arg
- hydrogen
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims description 4
- 239000003146 anticoagulant agent Substances 0.000 title description 6
- 229960004676 antithrombotic agent Drugs 0.000 title description 3
- -1 phenylglycyl Chemical group 0.000 claims abstract description 77
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 231100000252 nontoxic Toxicity 0.000 claims description 4
- 230000003000 nontoxic effect Effects 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 19
- 241001465754 Metazoa Species 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 229940122388 Thrombin inhibitor Drugs 0.000 abstract description 3
- 208000007536 Thrombosis Diseases 0.000 abstract description 3
- 239000003868 thrombin inhibitor Substances 0.000 abstract description 3
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical group OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 abstract description 2
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 abstract 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 26
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
- 108090000190 Thrombin Proteins 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- 229960004072 thrombin Drugs 0.000 description 20
- 239000002253 acid Substances 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 150000003951 lactams Chemical class 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 239000004475 Arginine Substances 0.000 description 14
- 229960003121 arginine Drugs 0.000 description 14
- 229960002429 proline Drugs 0.000 description 14
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 13
- 235000009697 arginine Nutrition 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 9
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000011347 resin Substances 0.000 description 9
- 229920005989 resin Polymers 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 108010016626 Dipeptides Proteins 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 125000004185 ester group Chemical group 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 6
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 5
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 5
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 210000001715 carotid artery Anatomy 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 229960000187 tissue plasminogen activator Drugs 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 230000002785 anti-thrombosis Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000000434 field desorption mass spectrometry Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- OXFGRWIKQDSSLY-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinolin-2-ium-1-carboxylate Chemical class C1=CC=C2C(C(=O)O)NCCC2=C1 OXFGRWIKQDSSLY-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 3
- DRERATFPWHSPRB-LEWJYISDSA-N benzyl (2s)-1-[(2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-2-phenylacetyl]pyrrolidine-2-carboxylate Chemical compound O=C([C@@H]1CCCN1C(=O)[C@H](NC(=O)OC(C)(C)C)C=1C=CC=CC=1)OCC1=CC=CC=C1 DRERATFPWHSPRB-LEWJYISDSA-N 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000035602 clotting Effects 0.000 description 3
- 239000000701 coagulant Substances 0.000 description 3
- 235000001671 coumarin Nutrition 0.000 description 3
- 125000000332 coumarinyl group Chemical class O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 3
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- KMTRFKAFNRHBCH-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1h-isoquinoline-1-carboxylic acid Chemical compound C1=CC=C2C(C(O)=O)N(C(=O)OC(C)(C)C)CCC2=C1 KMTRFKAFNRHBCH-UHFFFAOYSA-N 0.000 description 2
- 206010003178 Arterial thrombosis Diseases 0.000 description 2
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108010094028 Prothrombin Proteins 0.000 description 2
- 102100027378 Prothrombin Human genes 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 108010023197 Streptokinase Proteins 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 102000002262 Thromboplastin Human genes 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 2
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 2
- HDELGKMVZYHPPB-FJXQXJEOSA-N [(4s)-4-carboxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]butyl]-(diaminomethylidene)azanium;chloride Chemical compound Cl.CC(C)(C)OC(=O)N[C@H](C(O)=O)CCCN=C(N)N HDELGKMVZYHPPB-FJXQXJEOSA-N 0.000 description 2
- 159000000021 acetate salts Chemical class 0.000 description 2
- VXDSLUMUNWTSDB-UHFFFAOYSA-N acetic acid;chloroform;methanol Chemical compound OC.CC(O)=O.ClC(Cl)Cl VXDSLUMUNWTSDB-UHFFFAOYSA-N 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-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
- 230000000903 blocking effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- XAAKCCMYRKZRAK-UHFFFAOYSA-N isoquinoline-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=NC=CC2=C1 XAAKCCMYRKZRAK-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940039716 prothrombin Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960005202 streptokinase Drugs 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 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 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960005356 urokinase Drugs 0.000 description 2
- HOBFSNNENNQQIU-SNVBAGLBSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-2-phenylacetic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 HOBFSNNENNQQIU-SNVBAGLBSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- LHJGJYXLEPZJPM-UHFFFAOYSA-N 2,4,5-trichlorophenol Chemical compound OC1=CC(Cl)=C(Cl)C=C1Cl LHJGJYXLEPZJPM-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- LJCWONGJFPCTTL-UHFFFAOYSA-N 4-hydroxyphenylglycine Chemical compound OC(=O)C(N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 108700023418 Amidases Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- 108010048897 LY 287045 Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 102000005922 amidase Human genes 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 239000004019 antithrombin Substances 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- NEDMOHHWRPHBAL-MERQFXBCSA-N benzyl (2s)-pyrrolidin-1-ium-2-carboxylate;chloride Chemical compound Cl.O=C([C@H]1NCCC1)OCC1=CC=CC=C1 NEDMOHHWRPHBAL-MERQFXBCSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- QDHFHIQKOVNCNC-UHFFFAOYSA-N butane-1-sulfonic acid Chemical compound CCCCS(O)(=O)=O QDHFHIQKOVNCNC-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 230000001112 coagulating effect Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical group [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- VCMGMSHEPQENPE-UHFFFAOYSA-N ketamine hydrochloride Chemical compound [Cl-].C=1C=CC=C(Cl)C=1C1([NH2+]C)CCCCC1=O VCMGMSHEPQENPE-UHFFFAOYSA-N 0.000 description 1
- 229940124280 l-arginine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- XJJBXZIKXFOMLP-ZETCQYMHSA-N tert-butyl (2s)-pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1CCCN1 XJJBXZIKXFOMLP-ZETCQYMHSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- 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
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- External Artificial Organs (AREA)
- Inert Electrodes (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US58955390A | 1990-09-28 | 1990-09-28 | |
US75609191A | 1991-09-06 | 1991-09-06 |
Publications (3)
Publication Number | Publication Date |
---|---|
NO913773D0 NO913773D0 (no) | 1991-09-26 |
NO913773L NO913773L (no) | 1992-03-30 |
NO309984B1 true NO309984B1 (no) | 2001-04-30 |
Family
ID=27080589
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO913773A NO309984B1 (no) | 1990-09-28 | 1991-09-26 | AnalogifremgangsmÕte for fremstilling av tripeptidantitrombotiske midler |
Country Status (22)
Country | Link |
---|---|
EP (4) | EP0479489B1 (hu) |
JP (1) | JP3023019B2 (hu) |
KR (1) | KR100219993B1 (hu) |
CN (1) | CN1036399C (hu) |
AT (2) | ATE211147T1 (hu) |
AU (1) | AU645347B2 (hu) |
BR (1) | BR9104181A (hu) |
CA (1) | CA2052013C (hu) |
CZ (1) | CZ285980B6 (hu) |
DE (2) | DE69132884T2 (hu) |
DK (1) | DK0685489T3 (hu) |
ES (2) | ES2194835T3 (hu) |
FI (1) | FI107733B (hu) |
HU (2) | HU217441B (hu) |
IE (1) | IE913423A1 (hu) |
IL (1) | IL99527A (hu) |
MX (1) | MX9101280A (hu) |
NO (1) | NO309984B1 (hu) |
NZ (1) | NZ239907A (hu) |
PT (1) | PT99068B (hu) |
RU (1) | RU2077538C1 (hu) |
SK (1) | SK281731B6 (hu) |
Families Citing this family (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6008217A (en) * | 1995-12-20 | 1999-12-28 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
US5874424A (en) * | 1995-12-20 | 1999-02-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
US6204261B1 (en) | 1995-12-20 | 2001-03-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β Converting enzyme inhibitors |
US5430023A (en) * | 1990-09-28 | 1995-07-04 | Eli Lilly And Company | Tripeptide antithrombotic agents |
CA2071621C (en) * | 1991-06-19 | 1996-08-06 | Ahihiko Hosoda | Aldehyde derivatives |
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 |
US5416093A (en) * | 1991-11-12 | 1995-05-16 | Eli Lilly And Company | Antithrombotic agents |
US5760235A (en) * | 1992-03-04 | 1998-06-02 | Gyogyszerkutato Intezet Kft. | Anticoagulant peptide derivatives and pharmaceutical compositions containing the same as well as a process for preparation thereof |
US5583146A (en) * | 1992-12-02 | 1996-12-10 | Bristol-Myers Squibb Company | Heterocyclic thrombin inhibitors |
US5455229A (en) * | 1992-12-23 | 1995-10-03 | Eli Lilly And Company | Method for minimizing and containing ischemic and reperfusion injury |
US5672582A (en) * | 1993-04-30 | 1997-09-30 | Merck & Co., Inc. | Thrombin inhibitors |
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 |
US5780631A (en) * | 1993-06-03 | 1998-07-14 | Astra Aktiebolag | Starting materials in the synthesis of thrombin and kininogenase inhibitors |
SE9301916D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | New peptides derivatives |
US6984627B1 (en) | 1993-06-03 | 2006-01-10 | Astrazeneca Ab | Peptide derivatives |
US5462964A (en) * | 1993-10-20 | 1995-10-31 | The Du Pont Merck Pharmaceutical Company | Dipeptide boronic acid inhibitors of trypsin-like enzymes |
US5488037A (en) * | 1994-03-04 | 1996-01-30 | Eli Lilly And Company | Antithrombotic agents |
US5602101A (en) * | 1994-03-04 | 1997-02-11 | Eli Lilly And Company | Antithrombotic agents |
ZA951617B (en) * | 1994-03-04 | 1997-02-27 | Lilly Co Eli | Antithrombotic agents. |
JPH09509943A (ja) * | 1994-03-04 | 1997-10-07 | イーライ・リリー・アンド・カンパニー | 抗血栓剤 |
US5707966A (en) * | 1994-03-04 | 1998-01-13 | Eli Lilly And Company | Antithrombotic agents |
US5439888A (en) * | 1994-03-04 | 1995-08-08 | Eli Lilly And Company | Antithrombotic agents |
US5885967A (en) * | 1994-03-04 | 1999-03-23 | Eli Lilly And Company | Antithrombotic agents |
US5726159A (en) * | 1994-03-04 | 1998-03-10 | Eli Lilly And Company | Antithrombotic agents |
GB2287027A (en) * | 1994-03-04 | 1995-09-06 | Lilly Co Eli | Tripeptide antithrombotic agents |
CA2143533A1 (en) * | 1994-03-04 | 1995-09-05 | Kenneth D. Kurz | Antithrombotic agents |
US5436229A (en) * | 1994-03-04 | 1995-07-25 | Eli Lilly And Company | Bisulfite adducts of arginine aldehydes |
US5484772A (en) * | 1994-03-04 | 1996-01-16 | Eli Lilly And Company | Antithrombotic agents |
ZA951618B (en) * | 1994-03-04 | 1996-08-27 | Lilly Co Eli | Antithrombotic agents |
US5705487A (en) * | 1994-03-04 | 1998-01-06 | Eli Lilly And Company | Antithrombotic agents |
US5756466A (en) * | 1994-06-17 | 1998-05-26 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1β converting enzyme |
US6420522B1 (en) | 1995-06-05 | 2002-07-16 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
DE4421052A1 (de) | 1994-06-17 | 1995-12-21 | Basf Ag | Neue Thrombininhibitoren, ihre Herstellung und Verwendung |
US5847135A (en) * | 1994-06-17 | 1998-12-08 | Vertex Pharmaceuticals, Incorporated | Inhibitors of interleukin-1β converting enzyme |
US5716929A (en) * | 1994-06-17 | 1998-02-10 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1β converting enzyme |
US5510369A (en) * | 1994-07-22 | 1996-04-23 | Merck & Co., Inc. | Pyrrolidine thrombin inhibitors |
SE9404196D0 (sv) * | 1994-12-02 | 1994-12-02 | Astra Ab | New antithrombotic formulation |
US5710130A (en) * | 1995-02-27 | 1998-01-20 | Eli Lilly And Company | Antithrombotic agents |
US5914319A (en) * | 1995-02-27 | 1999-06-22 | Eli Lilly And Company | Antithrombotic agents |
US5629324A (en) * | 1995-04-10 | 1997-05-13 | Merck & Co., Inc. | Thrombin inhibitors |
US5919765A (en) * | 1995-06-07 | 1999-07-06 | Cor Therapeutics, Inc. | Inhibitors of factor XA |
US5721214A (en) * | 1995-06-07 | 1998-02-24 | Cor Therapeutics, Inc. | Inhibitors of factor Xa |
US6022861A (en) * | 1995-06-07 | 2000-02-08 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
US6046169A (en) * | 1995-06-07 | 2000-04-04 | Cor Therapeutics, Inc. | Inhibitors of factor XA |
US6069130A (en) | 1995-06-07 | 2000-05-30 | Cor Therapeutics, Inc. | Ketoheterocyclic inhibitors of factor Xa |
US5843904A (en) * | 1995-12-20 | 1998-12-01 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1βconverting enzyme |
AR005245A1 (es) | 1995-12-21 | 1999-04-28 | Astrazeneca Ab | Prodrogas de inhibidores de trombina, una formulación farmaceutica que las comprende, el uso de dichas prodrogas para la manufactura de un medicamento y un procedimiento para su preparacion |
HU222199B1 (hu) * | 1996-06-05 | 2003-05-28 | Gyógyszerkutató Intézet Kft. | Véralvadásgátló hatású peptid-aldehid-származékok és a vegyületeket tartalmazó gyógyszerkészítmények |
US6245743B1 (en) | 1996-06-05 | 2001-06-12 | Cor Therapeutics, Inc. | Inhibitors of factor Xa |
HU224315B1 (hu) * | 1996-06-05 | 2005-07-28 | Gyógyszerkutató Intézet Kft. | Véralvadásgátló hatású peptidil-arginin-aldehid-származékok és a vegyületeket tartalmazó gyógyszerkészítmények |
US5798377A (en) * | 1996-10-21 | 1998-08-25 | Merck & Co., Inc. | Thrombin inhibitors |
WO1998051684A1 (en) | 1997-05-15 | 1998-11-19 | Eli Lilly And Company | Antithrombotic compound |
KR100689923B1 (ko) | 1998-01-26 | 2007-03-09 | 애보트 게엠베하 운트 콤파니 카게 | 트롬빈 억제제 |
KR100377557B1 (ko) * | 1999-02-12 | 2003-03-26 | 주식회사 엘지생명과학 | 아실 구아니딘 작용기를 갖는 선택적 트롬빈 억제제 |
AU2002230836A1 (en) | 2000-12-18 | 2002-07-01 | Merck & Co., Inc. | Benzylamine derivatives and their use as thrombin inhibitors |
US6528503B2 (en) | 2000-12-18 | 2003-03-04 | Merck & Co., Inc. | Thrombin inhibitors |
WO2002064559A2 (en) | 2001-02-09 | 2002-08-22 | Merck & Co., Inc. | Thrombin inhibitors |
CA2457436A1 (en) * | 2001-08-21 | 2003-02-27 | Sandor Bajusz | Peptide arginals and methods for treating disseminated intravascular coagulation |
US7084134B2 (en) | 2002-05-02 | 2006-08-01 | Merk & Co., Inc. | Thrombin inhibitors |
GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
Family Cites Families (5)
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 |
IL89770A (en) * | 1988-03-28 | 1994-12-29 | British Tech Group | Analgesic peptides and pharmaceutical compositions containing them and the process for the preparation of some such compounds |
DE3827415A1 (de) * | 1988-08-12 | 1990-02-15 | Behringwerke Ag | Peptidderivate, verfahren zu ihrer herstellung und ihre verwendung |
GB8823480D0 (en) * | 1988-10-06 | 1988-11-16 | Ciba Geigy Ag | Antidote |
-
1991
- 1991-09-19 IL IL9952791A patent/IL99527A/xx active IP Right Grant
- 1991-09-23 CA CA002052013A patent/CA2052013C/en not_active Expired - Fee Related
- 1991-09-23 NZ NZ239907A patent/NZ239907A/en unknown
- 1991-09-23 CZ CS912913A patent/CZ285980B6/cs not_active IP Right Cessation
- 1991-09-23 HU HU037/91A patent/HU217441B/hu not_active IP Right Cessation
- 1991-09-23 SK SK2913-91A patent/SK281731B6/sk unknown
- 1991-09-26 AT AT95201960T patent/ATE211147T1/de not_active IP Right Cessation
- 1991-09-26 AU AU84780/91A patent/AU645347B2/en not_active Ceased
- 1991-09-26 DE DE69132884T patent/DE69132884T2/de not_active Expired - Fee Related
- 1991-09-26 NO NO913773A patent/NO309984B1/no unknown
- 1991-09-26 EP EP91308785A patent/EP0479489B1/en not_active Expired - Lifetime
- 1991-09-26 ES ES91308785T patent/ES2194835T3/es not_active Expired - Lifetime
- 1991-09-26 EP EP97203616A patent/EP0837071A1/en not_active Withdrawn
- 1991-09-26 EP EP95201960A patent/EP0685489B1/en not_active Expired - Lifetime
- 1991-09-26 DE DE69133217T patent/DE69133217T2/de not_active Expired - Fee Related
- 1991-09-26 DK DK95201960T patent/DK0685489T3/da active
- 1991-09-26 ES ES95201960T patent/ES2169105T3/es not_active Expired - Lifetime
- 1991-09-26 AT AT91308785T patent/ATE234857T1/de not_active IP Right Cessation
- 1991-09-26 EP EP95201959A patent/EP0684258A2/en not_active Ceased
- 1991-09-26 PT PT99068A patent/PT99068B/pt not_active IP Right Cessation
- 1991-09-26 RU SU5001658/04A patent/RU2077538C1/ru not_active IP Right Cessation
- 1991-09-26 MX MX9101280A patent/MX9101280A/es not_active IP Right Cessation
- 1991-09-26 KR KR1019910016772A patent/KR100219993B1/ko not_active IP Right Cessation
- 1991-09-27 IE IE342391A patent/IE913423A1/en not_active Application Discontinuation
- 1991-09-27 CN CN91109042A patent/CN1036399C/zh not_active Expired - Fee Related
- 1991-09-27 JP JP3249093A patent/JP3023019B2/ja not_active Expired - Fee Related
- 1991-09-27 BR BR919104181A patent/BR9104181A/pt not_active Application Discontinuation
- 1991-09-27 FI FI914566A patent/FI107733B/fi active
-
1995
- 1995-06-22 HU HU95P/P00399P patent/HU211634A9/hu unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO309984B1 (no) | AnalogifremgangsmÕte for fremstilling av tripeptidantitrombotiske midler | |
EP0542525B1 (en) | Antithrombotic agents | |
RU2105010C1 (ru) | Трипептид или его фармацевтически приемлемые соли или сольваты, фармацевтическая композиция, обладающая ингибирующей активностью в отношении амидазы тромбина | |
AU670381B2 (en) | Thrombin inhibitors | |
US5252566A (en) | Antithrombotic agents | |
US5416093A (en) | Antithrombotic agents | |
JPH07278093A (ja) | 抗血栓物質 | |
NO317089B1 (no) | Kininogeninhibitorer | |
JP3970935B2 (ja) | 抗−凝固性のペプチジル‐アルギニンアルデヒド誘導体 | |
US5731413A (en) | Method of synthesis of peptidyl aldehydes | |
EP0790982B1 (en) | Methods of synthesis of peptidyl argininals | |
US20050070480A1 (en) | Peptide arginals and methods for treating disseminated intravascular coagulation | |
AU2002331654A1 (en) | Peptide arginals and methods for treating disseminated intravascular coagulation |