AU2002232533A1 - Process for making a thrombin inhibitor - Google Patents
Process for making a thrombin inhibitorInfo
- Publication number
- AU2002232533A1 AU2002232533A1 AU2002232533A AU3253302A AU2002232533A1 AU 2002232533 A1 AU2002232533 A1 AU 2002232533A1 AU 2002232533 A AU2002232533 A AU 2002232533A AU 3253302 A AU3253302 A AU 3253302A AU 2002232533 A1 AU2002232533 A1 AU 2002232533A1
- Authority
- AU
- Australia
- Prior art keywords
- acetate
- ethyl
- difluoro
- pyridyl
- solvent
- 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
- 238000000034 method Methods 0.000 title claims description 33
- 230000008569 process Effects 0.000 title claims description 28
- 229940122388 Thrombin inhibitor Drugs 0.000 title description 17
- 239000003868 thrombin inhibitor Substances 0.000 title description 17
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 title description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 47
- 239000000203 mixture Substances 0.000 claims description 46
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 41
- 239000002904 solvent Substances 0.000 claims description 33
- -1 N-(2,2- dimethoxyethyl)carbamoyl Chemical group 0.000 claims description 32
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 23
- 229940011051 isopropyl acetate Drugs 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 238000004519 manufacturing process Methods 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 16
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 16
- 230000008878 coupling Effects 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 12
- 238000005859 coupling reaction Methods 0.000 claims description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 12
- FUPNXLAWWSHZPJ-UHFFFAOYSA-N (3-fluoropyridin-2-yl)methanamine;dihydrochloride Chemical compound Cl.Cl.NCC1=NC=CC=C1F FUPNXLAWWSHZPJ-UHFFFAOYSA-N 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 239000007795 chemical reaction product Substances 0.000 claims description 10
- 239000010949 copper Substances 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- RTZZBUQTHNQTSR-UHFFFAOYSA-N 2,2-difluoro-2-pyridin-2-ylethanol Chemical compound OCC(F)(F)C1=CC=CC=N1 RTZZBUQTHNQTSR-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 229910052802 copper Inorganic materials 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 8
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 8
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 7
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 7
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 claims description 6
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 claims description 6
- QVGBDRDOWKIYHK-UHFFFAOYSA-N 3-fluoro-1-oxidopyridin-1-ium Chemical compound [O-][N+]1=CC=CC(F)=C1 QVGBDRDOWKIYHK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000012445 acidic reagent Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 6
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 6
- RZDXBFLRLZSAKK-UHFFFAOYSA-N benzenesulfonic acid;2,2-difluoro-2-pyridin-2-ylethanamine Chemical compound OS(=O)(=O)C1=CC=CC=C1.NCC(F)(F)C1=CC=CC=N1 RZDXBFLRLZSAKK-UHFFFAOYSA-N 0.000 claims description 6
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- YSLRWDAJQZZLAQ-UHFFFAOYSA-N 2,2-difluoro-2-pyridin-2-ylacetic acid Chemical compound OC(=O)C(F)(F)C1=CC=CC=N1 YSLRWDAJQZZLAQ-UHFFFAOYSA-N 0.000 claims description 4
- VZFPSCNTFBJZHB-UHFFFAOYSA-N 3-fluoropyridine-2-carbonitrile Chemical compound FC1=CC=CN=C1C#N VZFPSCNTFBJZHB-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910000091 aluminium hydride Inorganic materials 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 235000009518 sodium iodide Nutrition 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- 239000012320 chlorinating reagent Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229940086542 triethylamine Drugs 0.000 claims description 3
- 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 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical group CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 239000000243 solution Substances 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 19
- 239000007787 solid Substances 0.000 description 16
- 229960000583 acetic acid Drugs 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 9
- 239000011736 potassium bicarbonate Substances 0.000 description 9
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 208000007536 Thrombosis Diseases 0.000 description 7
- 239000003146 anticoagulant agent Substances 0.000 description 7
- BZVJOAISKWPBOF-UHFFFAOYSA-N ethyl 2-[[2-(2,2-dimethoxyethylamino)-2-oxoacetyl]amino]acetate Chemical compound CCOC(=O)CNC(=O)C(=O)NCC(OC)OC BZVJOAISKWPBOF-UHFFFAOYSA-N 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- QLRSPKRGYAGOEC-UHFFFAOYSA-N (3-fluoropyridin-2-yl)methanamine Chemical compound NCC1=NC=CC=C1F QLRSPKRGYAGOEC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000002585 base Substances 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
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- AHLZMMPDDACOQX-UHFFFAOYSA-N ethyl 2,2-difluoro-2-pyridin-2-ylacetate Chemical compound CCOC(=O)C(F)(F)C1=CC=CC=N1 AHLZMMPDDACOQX-UHFFFAOYSA-N 0.000 description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 239000008279 sol Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229940127218 antiplatelet drug Drugs 0.000 description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000003527 fibrinolytic agent Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 4
- 229960000103 thrombolytic agent Drugs 0.000 description 4
- GIUTUZDGHNZVIA-UHFFFAOYSA-N 2-(ethylamino)acetic acid;hydrochloride Chemical compound Cl.CCNCC(O)=O GIUTUZDGHNZVIA-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000001879 copper Chemical class 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 206010002388 Angina unstable Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 2
- 108010001014 Plasminogen Activators Proteins 0.000 description 2
- 102000001938 Plasminogen Activators Human genes 0.000 description 2
- 206010038563 Reocclusion Diseases 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
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 208000007814 Unstable Angina Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000002399 angioplasty Methods 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
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 229940075894 denatured ethanol Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000002319 fibrinogen receptor antagonist Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 229940127126 plasminogen activator Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 229960000187 tissue plasminogen activator Drugs 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
- 239000012588 trypsin Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- LFMWZTSOMGDDJU-UHFFFAOYSA-N 1,4-diiodobenzene Chemical compound IC1=CC=C(I)C=C1 LFMWZTSOMGDDJU-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- QRADKVYIJIAENZ-UHFFFAOYSA-N 1-[[bromo(difluoro)methyl]-ethoxyphosphoryl]oxyethane Chemical compound CCOP(=O)(C(F)(F)Br)OCC QRADKVYIJIAENZ-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical class CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-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
- JZUMPNUYDJBTNO-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 JZUMPNUYDJBTNO-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- TYKNQWWXUIYRSZ-UHFFFAOYSA-N 2,2-difluoro-2-pyridin-2-ylethanamine Chemical compound NCC(F)(F)C1=CC=CC=N1 TYKNQWWXUIYRSZ-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical class BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- CELKOWQJPVJKIL-UHFFFAOYSA-N 3-fluoropyridine Chemical compound FC1=CC=CN=C1 CELKOWQJPVJKIL-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 102100022298 Divergent paired-related homeobox Human genes 0.000 description 1
- 206010014498 Embolic stroke Diseases 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000902412 Homo sapiens Divergent paired-related homeobox Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 108010000775 Hydroxymethylglutaryl-CoA synthase Proteins 0.000 description 1
- 102100028888 Hydroxymethylglutaryl-CoA synthase, cytoplasmic Human genes 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 206010043647 Thrombotic Stroke Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- UXYZPZXYHIDOFR-UHFFFAOYSA-N [[2-(2,2-dimethoxyethylamino)-2-oxoacetyl]amino] acetate Chemical compound C(C)(=O)ONC(=O)C(NCC(OC)OC)=O UXYZPZXYHIDOFR-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 230000000326 anti-hypercholesterolaemic effect Effects 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 230000001269 cardiogenic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000011889 copper foil Substances 0.000 description 1
- BFVJNCGUHJXDJN-UHFFFAOYSA-L copper;2,2-difluoro-2-iodoacetate Chemical class [Cu+2].[O-]C(=O)C(F)(F)I.[O-]C(=O)C(F)(F)I BFVJNCGUHJXDJN-UHFFFAOYSA-L 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- GAFRWLVTHPVQGK-UHFFFAOYSA-N dipentyl sulfate Chemical class CCCCCOS(=O)(=O)OCCCCC GAFRWLVTHPVQGK-UHFFFAOYSA-N 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- ZTQSADJAYQOCDD-UHFFFAOYSA-N ginsenoside-Rd2 Natural products C1CC(C2(CCC3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OCC(O)C(O)C1O ZTQSADJAYQOCDD-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920000260 silastic Polymers 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 230000001732 thrombotic effect Effects 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
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 230000006439 vascular pathology Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- 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
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/83—Thioacids; Thioesters; Thioamides; Thioimides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
- C07D241/16—Halogen atoms; Nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
- C07D241/18—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
TITLE OF THE INVENTION
PROCESS FOR MAKING A THROMBIN INHIBITOR BACKGROUND OF THE INVENTION
Taguchi, et al., Tetrahedron Letters, vol. 27, no. 50, pp. 6103-6106 (1986) describe a method for preparing 2,2-difluoroesters by reacting activated iododifluoroacetate-copper with organic halides. Sato, et al. Chem. Pharm. Bull. Vol. 47 no. 7 pp. 1013-1016 (1999) describe a method for preparing alkenyl- and aryldifluoroacetate from ethyl bromodifluoroacetate and halogenated compounds using copper powder. Sato, et al. Chem. Pharm. Bull. Vol. 48 no. 7 pp. 1023-1025 (2000) describe reaction of ethyl bromodifluoroacetate with α,β-unsaturated carbonyl compounds in the presence of copper powder. Cockerill, et al. J. Chem. Soc, Perkin Trans. 1 2000, 2591-2599 describe coupling of 1,4-diidobenzene with the organozinc reagent derived from diethyl bromodifluoromethylphosphonate with copper catalysis. Fleitz, et al. Synthetic Communications vol. 30 no. 17 pp. 3171-3180 (2000) describe synthesis of ethyl 3-(2,2-difluoro-2-(2- pyridylethylamino)pyrazin(lH)-2-one-l-acetate from 3,4-dihydro-6-methyl-2,3- dioxo-l(2H)-pyrazineacetic acid ethyl ester.
The present invention provides an efficient process for preparing the thrombin inhibitor 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2- pyridyl)ethylamino)-6-chloropyrazin-2-one-l-acetamide and related compounds.
SUMMARY OF THE INVENTION
The invention comprises processes for making 2,2-difluoro-2-(2- pyridyl)-ethan-l-ol, ethyl 3-chloropyrazin(lH)-2-one-acetate and 2-aminomethyl-3- fluoropyridine, and coupling of these, and further transformation, to give 3-fluoro-2- pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-l- acetamide or related compounds.
DETAILED DESCRIPTION OF THE INVENTION The invention is a process for preparing 2,2-difluoro-2-(2-pyridyl)- ethan-1-ol, which comprises coupling 2-bromopyridine with ethyl 2-bromo-2,2- difluoroacetate, in the presence of metallic copper, preferably a non-active copper
powder, and a solvent, e.g. a non-reactive solvent such as dimethyl sulfoxide or, more preferably, dimethylformamide, to form 2,2-difluoro-2-(2-pyridyl)acetate.
The invention is also a process for reducing 2,2-difluoro-2-(2- pyridyl)acetate with a reducing agent, e.g., a borohydride or aluminium hydride reagent such as sodium borohydride, lithium borohydride, sodium aluminium hydride, or lithium aluminium hydride, in the presence of a solvent, e.g. an alcohol such as ethanol, to form the 2,2-difluoro-2-(2-pyridyl)-ethan-l-ol.
The invention also includes a process for preparing 2,2-difluoro-2-(2- pyridyl)ethylamine benzenesulfonate salt which comprises adding trifluoromethanesulfonic anhydride to a solution of 2,2-difluoro-2-(pyridyl)ethanol in acetonitrile, and thereafter adding an ammonium reagent such as aqueous ammonia and a solution of benzenesulfonic acid to form 2,2-difluoro-2-(2-pyridyl)ethylamine benzenesulfonate salt.
The invention also includes a process for preparing ethyl 2-{(N-(2,2- dimethoxyethyl)carbamoyl } carbon ylamino) acetate which comprises reacting ethyl glycine hydrochloric acid salt with ethyl oxalyl chloride in the presence of a first non- reactive solvent, e.g. isopropyl acetate, to form a reaction product, adding 2,2- dimethoxyethylamine to the reaction product to form ethyl 2-{(N-(2,2- dimethoxyethyl)carbamoyl}carbon ylamino) acetate, and precipitating the ethyl 2-{(N- (2,2-dimethoxyethyl)carbamoyl}carbon ylamino) acetate with a second non-reactive solvent, e.g. heptane.
The invention also includes a process for preparing ethyl 2-(2,3-dioxo- 1,4-dihydropyrazinyl) acetate which comprises cyclizing ethyl 2-{(N-(2,2- dimethoxyethyl)carbamoyl } carbon ylamino) acetate in the presence of an acid reagent such as trifluoroacetic acid in a solvent such as acetic acid.
The invention also includes a process for preparing ethyl 3- chloropyrazin(lH)-2-one-l -acetate which comprises reacting ethyl 2-(2,3-dioxo-l,4- dihydropyrazinyl)acetate with a chlorinating reagent, e.g. thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, a mixture of triphenylphosphine and N-chlorosuccinimide, and a mixture of tetrabutyl ammonium chloride and phosphorous pentoxide, in the presence of a non-reactive solvent, e.g. isopropyl acetate, 1,2-dichloroethane, toluene, dimethylformamide, ethyl acetate,
dichloromethane, chloroform, carbon tetrachloride, benzene, propionitrile, acetonitrile and methyl acetate, to form ethyl 3-chloropyrazin(lH)-2-one-l-acetate.
The invention also includes a process for preparing ethyl 3-(2,2- difluoro-2-(2-pyridylethylamino)pyrazin(lH)-2-one-l-acetate which comprises coupling ethyl 3-chloropyrazin(lH)-2-one-l -acetate with 2,2-difluoro-2-(2- pyridyl)ethylamine benzenesulfonate salt in the presence of a base, such as N,N diisopropylethylamine, triethyl amine, or tributyl amine, a non-reactive solvent such as acetonitrile, and an iodide, such as sodium iodide, to form ethyl 3-(2,2-difluoro-2- (2-pyridylethylamino)pyrazin(lH)-2-one-l -acetate. The invention is also a process for peparing 3-fluoro-2-pyridylmethyl-
3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-l-acetamide which comprises coupling
with 2-aminomethyl-3-fluoropyridine dihydrochloric acid salt in the presence of a coupling reagent such as l-(3-dimethylaminopropyl)-3-ethylcarbo-diimide hydrochloride or 1,3-dicyclocarbdiimide, optionally additionally including 1- hydroxybenzotriazole hydrate or l-hydroxy-7-azabenzotriazole, and a base such as potassium hydroxide, to form 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2- pyridyl)ethylamino)-6-chloropyrazin-2-one- 1 -acetamide.
The process includes, for example, preparing 3-fluoro-2- pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-l- acetamide by coupling ethyl 3-(2,2-difluoro-2-(2-pyridylethylamino)pyrazin(lH)-2- one-1-acetate with 2-aminomethyl-3-fluoropyridine dihydrochloric acid salt in the presence of a base such as potassium hydroxide to form 3-fluoro-2-pyridylmethyl-3- (2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-l-acetamide. The invention also includes a compound having the formula
wherein R is C1-.4 alkyl, e.g. -CH2CH3.
The invention also includes a process for recrystallizing 2- aminomethyl-3-fluoropyridine dihydrochloride which comprises suspending 2- aminomethyl-3-fluoropyridine dihydrochloride in acetic acid, heating to dissolve the 2-aminomethyl-3-fluoropyridine dihydrochloride into a solution, and precipitating the 2-aminomethyl-3-fluoropyridine dihydrochloride from the solution.
The invention also includes a process for preparing 2-{3-[(2,2- difluoro-2-(2-pyridyl)ethyl)amino]-6-chloro-2-oxohydro-pyrazinyl } acetate which comprises chlorinating ethyl 3-(2,2-difluoro-2-(2-pyridylethylamino)pyrazin(lH)-2- one-1-acetate with N-chlorosuccinimide or 1,3 dichloro-5,5-dimethylhydantoin in the presence of a non-reactive solvent such as acetonitrile.
The invention also includes a process for preparing 2-cyano-3- fluoropyridine comprising adding chlorotrimethylsilane to a mixture comprising 3- fluoropyridine N-oxide and potassium cyanide to form 2-cyano-3-fluoropyridine.
The invention also includes a process for preparing ethyl 2-(2,3-dioxo- l,4-dihydropyrazinyl)acetate which comprises preparing ethyl 2-{(N-(2,2- dimethoxyethyl)carbamoyl}carbonylamino) acetate by reacting ethyl glycine hydrochloric acid salt with ethyl oxalyl chloride in the presence of a first non-reactive solvent such isopropyl acetate to form a first reaction product, adding 2,2- dimethoxyethylamine to the first reaction product to form a second reaction product comprising ethyl 2-{(N-(2,2-dimethoxyethyl)carbamoyl }carbonylamino) acetate, and cyclizing ethyl 2- {(N-(2,2-dimethoxyethyl)carbamoyl} carbon ylamino) acetate in the presence of an acid reagent such as trifluoroacetate and a second solvent such as acetic acid to form ethyl 2-(2,3-dioxo-l,4-dihydropyrazinyl)acetate.
The abbreviations listed below are used in the specification and have the meanings indicated below:
BSA benzenesulfonic acid
- A -
CH3CN acetonitrile
CH3CO2H acetic acid
DMF dimethylformamide
DMSO dimethylsulfoxide
EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EtOH ethanol
Et3N triethylamine
HOBt 1-hydroxybenzotriazole hydrate
IPAc isopropyl acetate
KCN potassium cyanide
KHCO3 potassium hydrogen carbonate
KOH potassium hydroxide
MeCN acetonitrile
NaBH4 sodium borohydride
Nal sodium iodide
Na2CO3 sodium carbonate
NCS N-chlorosuccinimide
NMP N-methyl pyrrolidinone s.g. specific gravity
SOCI2 thionyl chloride
TFA trifluoroacetic acid
Tf2O trifluoromethane sulfonic anhydride
THF tetrahydrofuran
TMSC1 trimethylsilyl chloride
Metallic copper useful in the process of the invention includes activated and non activated copper, including copper bars, copper foil, copper granules, copper powder, copper rods, copper shots, copper turnings, and copper wire. Preferably, the copper is a non-activated metallic copper powder. Suitable non- activated copper powders include dendritic 3 micron, -40 mesh, -150 mesh, submicron, copper bronze, -200 mesh, and spheroidal powders.
The term "alkyl" includes branched or straight chain alkyl groups. "C1-.4 alkyl" refers to alkyl groups having 1, 2, 3, or 4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, etc.
Pharmaceutically-acceptable salts of compounds prepared according to the process of the invention (in the form of water- or oil-soluble or dispersible products) include the conventional non-toxic salts such as those derived from inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen- containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
In order to determine activity of compounds prepared according to the process of the invention, assays of human cc-thrombin and human trypsin were performed by the methods substantially as described in Thrombosis Research, Issue No. 70, page 173 (1993) by S.D. Lewis et al. Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration < 0.1 Km into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve
equilibration between enzyme and inhibitor were determined in control experiments. Initial velocities of product formation in the absence (V0) or presence of inhibitor (Vj) were measured. Assuming competitive inhibition, and that unity is negligible compared to Km/[S] and [I]/e (where [S], [I], and e respectively represent the total concentrations, of substrate, inhibitor and enzyme), the equilibrium constant (Kj) for dissociation of the inhibitor from the enzyme can be obtained from the dependence of VoNi on [I] shown in the equation: V0/Nj = 1 + [I]/Ki.
The activities shown by this assay indicate that the compounds are therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels. The compounds are selective compounds, as evidenced by their inhibitory activity against human trypsin (represented by Ki), which is at least 1000 nM. Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy. The term "patient" used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
Compounds prepared according to the process of the invention are useful for treating or preventing venous thromboembolism (e.g. obstruction or occlusion of a vein by a detached thrombus; obstruction or occlusion of a lung artery by a detached thrombus), cardiogenic thromboembolism (e.g. obstruction or occlusion of the heart by a detached thrombus), arterial thrombosis (e.g. formation of a thrombus within an artery that may cause infarction of tissue supplied by the artery), atherosclerosis (e.g. arteriosclerosis characterized by irregularly distributed lipid deposits) in mammals, and for lowering the propensity of devices that come into contact with blood to clot blood. The thrombin inhibitors can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups, and
emulsions. Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.
The thrombin inhibitors can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow-Corning Corporation.
The dosage regimen utilizing the thrombin inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
Oral dosages of the thrombin inhibitors, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably 0.1-0.5 mg/kg/day (unless specificed otherwise, amounts of active ingredients are on free base basis). For example, an 80 kg patient would receive between about 0.8 mg/day and 2.4 g/day, preferably 2-600 mg/day, more preferably 8-200 mg/day, and most preferably 8-40 mg/day. A suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg, 10 mg, 20 mg and 40 mg. Advantageously, the thrombin inhibitors may be administered in divided doses of two, three, or four times daily. For administration twice a day, a suitably
prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg.
Intravenously, the patient would receive the active ingredient in quantities sufficient to deliver between 0.025-7.5 mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day. Such quantities may be administered in a number of suitable ways, e.g. large volumes of low concentrations of active ingredient during one extended period of time or several times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g. once a day. Typically, a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg/ml, e.g. 0.1 mg/ml, 0.3 mg/ml, and 0.6 mg/ml, and administered in amounts per day of between 0.01 ml/kg patient weight and 10.0 ml/kg patient weight, e.g. 0.1 ml/kg, 0.2 ml/kg, 0.5 ml/kg. In one example, an 80 kg patient, receiving 8 ml twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg/ml, receives 8 mg of active ingredient per day. Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers. The choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art.
The compounds can also be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.
The thrombin inhibitors are typically administered as active ingredients in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixers, syrups and the like, and consistent with convention pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
Typical uncoated tablet cores suitable for administration of thrombin inhibitors are comprised of, but not limited to, the following amounts of standard ingredients:
Excipient General Range Preferred Range Most Preferred Range
(%) (%) (%) mannitol 10-90 25-75 30-60 microcrystalline 10-90 25-75 30-60 cellulose magnesium stearate 0.1-5.0 0.1-2.5 0.5-1.:
Mannitol, microcrystalline cellulose and magnesium stearate may be substituted with alternative pharmaceutically acceptable excipients.
The thrombin inhibitors can also be co-administered with suitable anti- platelet agents, including, but not limited to, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), anticoagulants such as aspirin, thrombolytic agents such as plasminogen
activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies, or lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as lovastatin or simvastatin, HMG CoA synthase inhibitors, etc.) to treat or prevent atherosclerosis. For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and thrombin inhibitors. Also, thrombin inhibitors enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion. Thrombin inhibitors may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter.
Typical doses of the thrombin inhibitors in combination with other suitable anti-platelet agents, anticoagulation agents, or thrombolytic agents may be the same as those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, or may be substantially less that those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient's therapeutic needs.
The following schemes are exemplary and should not be interpreted as limiting the scope of the invention as defined above.
SCHEMEl
SOCI2
IPAc
DMF
NCS MeCN
Ethyl 2-{ (N-(2,2-dimethoxyethyl)carbamoyl|carbonylamino)acetate (2)
A mixture of ethyl glycine.HCl (1, 40.0 g, 286 mmol), potassium bicarbonate (172 g, 1.72 mol), water (120 mL) and isopropyl acetate (440 mL) was treated at 0°C with ethyl oxalyl chloride (78.4 g, 574 mmol). More water (180 mL) was added and the organic phase was separated. The aqueous phase was re-extracted with isopropyl acetate (400 mL) and the combined organic phases concentrated to 300 mL volume. At 20 °C, 2,2-dimethoxyethylamine (37.7 g, 358 mmol) was added and after 16 hours, the solution was concentrated to 100 mL and diluted with heptane (400 mL). The solid was collected and washed with heptane (90 mL) and dried to give crystalline oxamide 2 (65.7 g, 87% yield from 1). Melting point: 63 - 65 °C Proton NMR spectrum in methylene chloride d2 at 400MHz on Bruker DRX400 spectrometer, s = singlet, d = doublet, t = triplet, q = quartet, b = broad. 7.78ppm, bt, 1H; 7.42ppm bt, ~5Hz, 1H; 4.30ppm, t, 5.27Hz, 1H; 4.10ppm, q, 7.14Hz, 2H; 3.94ppm, d, 5.91Hz, 2H; 3.32ppm, dd, 5.26Hz, 6.22Hz, 2H;3.25ppm, s, 6H; 1.15ppm, t, 7.14Hz, 3H.
Ethyl 2-(2,3-dioxo-L4-dihydropyrazinyl)acetate (3)
Trifluoroacetic acid (4.7 g, 41.5 mmol) was added to a mixture of ethyl 2-{ (N-(2,2-dimethoxyethyl)carbamoyl}carbonylamino acetate 2 (10 g, 38.1 mmol) and acetic acid (25 mL). The stirred mixture was heated at 78 °C (internal temperature) and aged for 3 hours 45 minutes. The dark mixture was allowed to cool to 20 °C and stirred for 30 minutes before dilution with ethyl acetate (130 mL) and toluene (100 mL). After ageing at 20 °C for 30 minutes, the mixture was cooled to 5 °C and aged for a further 90 minutes. The product was collected by filtration, washed with ethyl acetate (50 ml), air dried and dried in vacuo at 45 °C to afford the title compound (3, 5.53 g, 73 % yield) as a crystalline solid.
Melting point: 150 - 152 °C; crystalline by XRPD
Proton NMR spectrum in methanol t at 400MHZ on Bruker DRX400 spectrometer. s = singlet, d = doublet, t = triplet, q = quartet.
6.51ppm, d, 5.96Hz, 1H; 6.38ppm, d, 5.96, 1H; 4.78ppm, s, 2H; 4.22ppm, q, 7.15Hz, 2H; 1.28ppm, t, 7.15Hz, 3H.
Ethyl 2-(2-3-dioxo-l-4-dihydropyrazinyl)acetate (3) (alternative process)
The following alternative procedure produces 3 directly from ethyl glycine hydrochloride L This process avoids the need for isolating ethyl 2-{ (N-(2,2- dimethoxyethyl)carbamoyl}carbonylamino) acetate 2.
A mixture of potassium hydrogen carbonate (43 kg), water (15 L), isopropyl acetate (110 L) and ethyl glycine hydrochloride salt 1 (10 kg) were stirred together and cooled to 0° C. Ethyl oxalyl chloride (19.6 kg) was then added to the stirred mixture, at 0° C, over 2.3 h. More water (60 L) was added, the phases were separated and the aqueous phase was re-extracted with more isopropyl acetate (100
L). The combined isopropyl acetate extracts were concentrated to a volume of 130 L. and then 2,2-dimethoxyethylamine (9.43 kg) was added. The solution was stirred for
18 h. The resulting solution of the oxamide 2 was then washed successively with a solution of citric acid (5 kg) in water (10 L), and then with a solution of
potassium hydrogen carbonate (1.75 kg) in water (6.25 L). The resulting organic solution was then concentrated to a volume of 30 L and diluted with acetic acid (80 L). This solution was again concentrated at reduced pressure to a volume of 40 L. Acetic acid (15 L) and trifluoroacetic acid (5.1 L) were charged and the resulting solution heated to 78° C for 3.5 h.
To the cooled solution was then added isopropyl acetate (214 L) followed by toluene (165 L). The slurry was stirred and cooled to 0-5° C for 1 h and the solid collected by filtration. The solid was washed with toluene and dried to give 10.66 kg of the crystalline ester 3.
Ethyl 3-chloropyrazin(lH)-2-one-l-acetate 5
A mixture of ethyl 2-(2,3-dioxo-l,4-dihydropyrazinyl)acetate 3 (20 g,
100 mmol), isopropyl acetate (40 mL) and DMF (20 mL) was warmed to 45 °C. To the mixture was added thionyl chloride (12.87 g) slowly over 10 minutes. The temperature was raised to 55-60°C. The chlorination was complete after 2hrs. the reaction was diluted with isopropyl acetate (140 mL) and cooled to 30°C. 2M KHCO3 (150 mL) was added slowly over 5 minutes. The two layers were separated, the aqueous phase was back-extracted with isopropyl acetate (90 mL). The combined organic phase was successively washed with 2 M KHCO3 (50 mL) and water (2 x 50 mL). The organic phase was concentrated down to dryness in vacuo. The resulting yellow solid was flushed with tert-butyl methyl ether (2 x20 mL). The solid was dried in vacuo at room temperature to afford the title compound 5 (19.4 g, 89% yield from 3).
Melting point: 47-49 °C; crystalline by XRPD
Proton spectrum in methylene chloride d2, at 400 MHz on Bruker DRX 400, with tetramethylsilane as internal reference, d = doublet, t = triplet, s = singlet, q = quartet.
7.14ppm, d, 4.4Hz, 1H; 7.12ppm, d, 4.4Hz, 1H; 4.64ppm, s, 2H; 4.24ppm, q, 7.15Hz, 2H; 1.28ppm, t, 7.15Hz,3H.
Ethyl 3-chloropyrazin(lH)-2-one-l-acetate 5 (not isolated)
A mixture of ethyl 2-(2,3-dioxo-l,4-dihydropyrazinyl)acetate 3 (10 g, 50 mmol), isopropyl acetate (10 mL) and DMF (5 mL) was heated to 48-50°C and a solution of thionyl chloride (6.6 g, 55.5 mmol) in isopropyl acetate (15 mL) added drop-wise. After the addition the temperature was increased to 55-60°C. The reaction initially formed a yellow-orange slurry, but within ten minutes a clear red solution was generated and the chlorination was complete after 1.5 hours. The mixture was allowed to cool to room temperature and isopropyl acetate (70 mL) was added before the reaction was quenched by the addition of KHCO3 (75 mL of a 2 M aq sol). The two layers were separated, and the organic phase washed with KHCO3 (32.5 mL), brine (32.5 mL) and water (6 mL). The organic phase was concentrated in vacuo to - 15 mL and the solution flushed with acetonitrile (3 x 50 mL). Acetonitrile (24 mL) was added to give a crude solution of the ethyl 3-chloropyrazin(lH)-2-one-l-acetate 5 (9.7 g assay yield).
Ethyl 3-(2,2-difluoro-2-(2-pyridylethylamino)ρyrazin(lH)-2-one-l-acetate (8)
To the solution above was added the 2,2-difluoro-2-(2-pyridyl) benzenesulfonic acid 7 (the synthesis of which is described below)(14.28 g, 99.5 wt/wt%, 44.9 mmol), followed by NN-diisopropylethyla ine (5.8 g, 44.9 mmol) and sodium iodide (13.47 g, 89.8 mmol). The mixture was heated to reflux and aged for 24 hours and then cooled to room temperature. N.N-Diisopropylethylamine (5.8 g,
44.9 mmol) was added, followed by the slow addition of water (120 mL) during which crystallization of the product occurred. The slurry was cooled in an ice-bath at 0°C for one hour and then filtered. After washing with water (3 x 40 mL) the product was dried in vacuo at 45°C to afford the title compound 8 (12.76 g, 75% yield from 3) as crystalline needles.
Melting point: 92 - 94 °C; crystalline by XRPD
Proton NMR spectrum in methylene chloride d at 400MHz on Bruker DRX400 spectrometer, s = singlet, d = doublet, t = triplet, q = quartet, b = broad., 8.66ppm, ddt, 0.87, 1.67, 4.77Hz, IH; 7.84ppm, dt, 1.75, 7.79Hz, IH; 7.68ppm, dt, 1.03, 7.87Hz, IH; 7.41ppm, m, IH; 6.81ppm, d, 4.61Hz, IH; 6.50ppm bt, 6.6Hz, IH; 6.44ppm, d, 4.61Hz, IH; 4.52ρρm, s, 2H; 4.34ppm, dt, 6.6, 14.4Hz, 2H; 4.21ppm, q, 7.07Hz, 2H; 1.26ppm, t, 7.07Hz, 3H.
Ethyl 2-{3-r.2.2-difluoro-2-(2-pyridyl)ethyl)amino1-6-chloro-2-oxohvdro- pyrazinyl I acetate (9)
The ester 8 (20.0 g, 59.2 mmol) was slurried in acetonitrile (100 mL) and the mixture heated to 65 °C to give a solution. A solution of N-chlorosuccinimide (8.29 g, 62.1 mmol) in acetonitrile (100 mL) was then added over 10 minutes after which the reaction was maintained at 70 °C for 1 hour. The reaction mixture was cooled to 8 °C and water (450 mL) added drop-wise. The resulting mixture was aged at 5 °C for 1 hour and the solid collected by filtration. The product was washed with water (500 mL), air dried and dried in vacuo at 45 °C to give the title compound 9 (20.1 g, 91% yield) as a crystalline solid.
Melting point: 102 - 105 °C. Crystalline by XRPD
Proton spectrum in methylene chloride d2, at 250 MHz on Bruker DPX 250, with tetramethylsilane as internal reference, d = doublet, t = triplet, s = singlet, q = quartet. 8.65ppm, d, 5.0 Hz, IH; 7.85ppm, dt, 1.9, 7.5 Hz, IH; 7.68ppm, dt, 1.25, 7.8 Hz, IH; 7.40ppm, m, IH; 6.92ppm, s, IH; 6.55ppm, bt, 6.3 Hz, IH; 4.89ppm, s, 2H; 4.34ppm, dt, 6.6, 14.4 Hz, 2H; 4.22ppm, q, 7.0 Hz, 2H; 1.25ppm, t, 7.0 Hz, 3H.
3-Fluoro-2-pyridylmethyl-3-(2-2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin- 2-one-l-acetamide H?O (12)
The chloroester 9 (3.15 kg, 8.45 mol) was dissolved in THF (85 L) and treated with potassium hydroxide (19.4 L of 1 M aq sol) after which the two-phase mixture was stirred at 40 °C for 4 hours. HOBt ( 1.14 kg, 8.45 mol) and amine.2HCl ϋ (1.79 kg, 8.87 mol) were added followed by the slow addition of a solution of EDC.HC1 (2.02 kg, 10.6 mol) in THF (10 L) over 1.75 hours with the reaction temperature maintained at 40 °C. After a further 1 hour at this temperature, the reaction was allowed to cool to room temperature during which time crystallisation occurred. This was completed by addition of sodium bicarbonate (100 L of 3.5% aq sol). The product was collected by filtration, washed well with water (20 L), air dried and dried in vacuo at 45 °C to afford i2 (3.77 kg, 95%) as a mixture of monohydrates. Melting point: 182 °C Proton spectrum in methylene chloride d at 250 MHz on Bruker DPX 250, with tetramethylsilane as internal reference, d = doublet, t = triplet, s = singlet, q = quartet. 8.66ppm, d, 5.0 Hz, IH; 8.34ppm, dt, 1.6, 4.7 Hz, IH; 7.85ppm, dt, 1.6, 7.5 Hz, IH; 7.68ppm, dt, 1.2, 7.8 Hz, IH; 7.43ppm, m, 2H; 7.26ppm, m, IH; 7.23ppm,
bs, IH; 6.98ppm, s, IH; 6.51ppm, bt, 6.3 Hz, IH; 4.88ppm, s, 2H; 4.652ppm, dd, 1.6, 4.7 Hz, 2H; 4.34ppm, dt, 6.6, 14.4 Hz, 2H.
3-Fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin- 2-one-l-acetamide Anhydrous A
A mixture of 2 (3.69 kg, 7.85 mol) and ethanol (140 L) was heated to reflux with a solution resulting when the internal temperature reached 78 °C. The solution was allowed to cool to 67 °C when it was seeded with compound 2 anhydrous A (73g, 0.15 mol). The resulting mixture was cooled to 40 °C and then 90 L of ethanol was removed by in vacuo distillation before allowing to cool to room temperature then stirring for 16 hours. The mixture was cooled to -5 °C then the product was collected by filtration and dried in vacuo at 50 °C to afford 3-fluoro-2-ρyridylmethyl-3-(2,2-difluoro-2-(2- pyridyl)ethylamino)-6-chloropyrazin-2-one-l-acetamide anhydrous A (3.46 kg, 7.66 mol, 96% recovery).
3-Fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin- 2-one-l-acetamide Monohydrate A
A mixture of 12 (20.0 g, 42.5 mmol) and aqueous ethanol (600 mL of 1 : 1 ethanol: water mixture) was heated to reflux during which dissolution occurred. The solution was cooled to 68 °C then 3-fluoro-2-pyridylmethyl-3-(2,2- difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-l-acetamide monohydrate A (0.05 g, 0.10 mmol) was added as seed. The resulting mixture was allowed to cool to room temperature over 1 hour and then cooled to 2 °C before the product was collected by filtration and dried under a stream of nitrogen at ambient temperature to afford the title compound (18.70 g, 93% recovery).
3-Fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethyIamino)-6-chloropyrazin- 2-one-l-acetamide Monohydrate B
A mixture of 2 (20.0 g, 42.5 mmol) and aqueous ethanol (400 mL of 4: 1 ethano water mixture) was heated to 70 °C after which dissolution occurred. The solution was allowed to cool to room temperature over 16 hours then a further addition of water (320 mL) was made before the product was collected by filtration and dried under a stream of nitrogen at ambient temperature to afford the title compound (19.45 g, 97% recovery).
SCHEME 2
Cu powder, DMSO, 40 °C
NaBH4, EtOH
'
1) Tf20, pyridine, MeCN
2) aq NH3, benzenesulfonic acid
Ethyl 2.2-difluoro-2-(2-pyridyl)acetate (13)
13
2-Bromoρyridine (14.7 kg, 92.8 mol), ethyl 2-bromo-2,2- difluoroacetate (19.5 kg, 96.1 mol) and copper bronze (12.4 kg, 195 mol) were slurried in DMSO (74 L) and heated to 40 °C. After 4 hours at this temperature, isopropyl acetate (119 L) was added and the reaction cooled to 5 °C. A previously prepared, cooled (5 °C) solution of potassium dihydrogenphosphate (27.8 kg, 204 mol) in water (147 L) was added over 20 minutes, maintaining the temperature <15°C. The two-phase mixture was aged for 30 minutes then the aqueous layer was discarded. The organic extract was washed with water (59 L) and then distilled to residue under reduced pressure to give the title compound 13 (15.3 kg, 82% yield).
Ethyl 2,2-difluoro-2-(2-pyridyl)acetate (13) (alternative process)
Copper powder (lOO.Og) was slurried in DMF (500ml) with 2-bromopyridine (lOO.Og) and ethyl bromodifluoroacetate (133.3g) and warmed to 50 °C. The mixture was kept at between 50 °C and 52 °C for 8.5 hours, HPLC indicating no 2-bromopyridine remaining. The reaction mixture was diluted with isopropyl acetate (750ml) and cooled to 5 °C. A solution of potassium dihydrogen phosphate (190.7g) in water (1100ml) was added to the dimethylformamide/isopropyl acetate mixture at below 30 °C and well stirred for 30 minutes. The mixture was filtered to remove the precipitated copper salts giving a two phase filtrate. The solid was washed with isopropyl acetate (2 x 330mL) and the washes combined with the filtrate. The layers were separated and the top organic layer washed twice with water (2 x 500ml). Under reduced pressure the organic layer was evaporated to a volume of 300mL, ethanol (400mL) added, the volume reduced to 300mL, again ethanol (400mL) added, again
the volume reduced to 300mL then made up to 600mL with ethanol. The required title compound O (103.15g) was obtained in 81.0% yield.
2.2-Difluoro-2-(2-pyridyl)ethan-l-ol (6)
6
Ethyl 2,2-difluoro-2-(2-pyridyl)acetate (15.3 kg, 76.0 mol) (used as is from previous step) was dissolved in anhydrous ethanol (35 L) and filtered through a 1 μ in-line filter into the vessel. Further alcohol (41 L) was used to rinse the lines. The batch was cooled to 5 °C and then sodium borohydride
(2.88 kg, 76.0 mol) was added in 5 portions over 1 h, maintaining the temperature at <30 °C. After the addition, the batch was aged for 1.5 h and then quenched by the careful addition of hydrochloric acid (55 L, 2 M aq sol) and then concentrated by vacuum distillation. The resulting aqueous solution was basified to pH 8.5 by the addition of sodium hydroxide solution (4.8 L, 46/48% w/w) and then extracted with ethyl acetate (56 L + 28 L). The combined organic extracts were distilled to low volume (20 L) and then heptane (84 L) was added over 30 min, which induced crystallisation. The slurry was cooled to 5 °C, aged for 1 h and then filtered. The filter cake was washed with heptane (5 L) and then dried overnight in vacuo at 30 °C, to give the title compound 6 (11.7 kg, 76% yield over 2 steps from 2-bromopyridine) as crystalline cream plates. Melting point: 58-60 °C; crystalline by XRPD
Proton NMR spectrum in methylene chloride d2 at 400MHZ on Bruker DRX400 spectrometer, s = singlet d = doublet, t = triplet, q = quartet, b = broad. 8.60ppm dddt, 0.8,1.7,4.8Hz, IH; 7.89ppm, dt, 1.7, 7.7Hz, IH; 7.71ppm, dt, 1.2, 7.7Hz, IH; 7.44ppm, ddq, 0.8, 1.2, 7.7Hz, IH; 4.19ppm, t, 12.7, 2H; 3.65ppm, bs, IH.
2,2-Difluoro-2-(2-pyridyl)ethylamine.benzenesulfonate salt (7)
To a cooled (5 °C) solution of 2,2-difluoro-2-(pyridyl)ethanol 6
(20.0 g, 126 mmol), pyridine (13.2 mL, 163 mmol) and acetonitrile (200 mL) was added trifluoromethane sulfonic anhydride (39.0 g, 138 mmol) with the internal temperature kept below 18 °C. The resulting mixture was stirred at 10 °C for 30 minutes and HPLC analysis indicated the reaction was complete. Maintaining the temperature below 18 °C, concentrated aqueous ammonia (s.g. 0.88, 200 mL) was added and the mixture was allowed to stir at room temperature for 16 hours. The orange solution was then evaporated in vacuo to a volume of approximately 200 mL. The dark aqueous solution was basified to pH14 with 48% sodium hydroxide solution (20 mL) and extracted with methylene chloride (2 x 200 mL). The methylene chloride extracts were combined and evaporated to a volume of 200 mL. A solution of benzenesulfonic acid (17.3 g; 108 mmol) in ethyl acetate (173 mL) was added over 1 hour at room temperature during which time crystallisation of the salt ensued. The mixture was cooled in ice for 1 hour and then the solid was filtered, washed with ethyl acetate (2 x 40 mL), dried in vacuo at 30 °C overnight to give the crystalline amine benzenesulfonate salt 7. (15.65 g, 79%). Methanol-d4. Proton spectrum at 400MHZ on Bruker DRX 400, with tetramethylsilane as internal reference, d = doublet, t = triplet, m = multiplet. 8.67ppm, ddd, 0.9, 1.7, 5.9Hz, IH; 8.30ppm, dt, 1.7, 7.7Hz, IH; 7.88-7.79ppm, m, 3H; 7.59, dddd, 0.9, 2.0, 4.9, 7.7Hz, IH; 7.46-7.38ppm, m, 3H; 3.91, t, 14.4Hz, 2H.
SCHEME 3
H2O2 CH3C02H
10
1) KCN, TMSCI, Et3N, DMF 2) H2) Pd/C, alcohol
3-Fluoropyridine N-oxide (10)
10
To a solution of 3-fluoropyridine (1.485 kg, 15.3 mol) in glacial acetic acid (12 L) at 100 °C was added 27% hydrogen peroxide solution (1.895 kg, 15.0 mol) dropwise over six hours. The solution was stirred overnight at the same temperature and the acetic acid/water then removed in vacuo. The residue was flushed in vacuo with toluene (6 x 8.4 L) before more toluene (12.2 L) was added followed by anhydrous potassium carbonate (1.023 kg, 7.4 mol). This mixture was stirred at 35 °C for 30 min and then filtered and the solids washed twice with warm (50 °C) toluene (2 x 4L). The filtrate plus washes were concentrated in vacuo to 5.0 L and this was then heated to 45 °C and heptane (6.3 L) was added over 10 min. The slurry was cooled to 0 °C then aged for 2 hr before filtering. The solid was washed with heptane (1.3 L) and dried in vacuo at 30 °C to give the N-oxide 10 as a white solid (1.456 kg, 84%). Proton spectrum in methylene chloride d2 at 250 MHz on Bruker DPRX 250. d = doublet, t = triplet, s = singlet, q = quartet.
8.03ppm, dt, 1.8, 4.7 Hz, IH; 7.92ppm, dd, 0.7, 6.5 Hz, IH; 7.15ppm,br q, 8.2 Hz, IH; 6.97ppm, td, 2.2, 7.0 Hz, IH.
2-Aminomethyl-3-fluoropyridine.2HCl (11)
Chlorotrimethylsilane (7.19 kg, 66 mol) was added dropwise over ten minutes to a mixture of N-oxide 10 (2.5 kg, 22 mol), potassium cyanide (2.16 kg, 33 mol), triethylamine (6.7 kg, 66 mol) and DMF (30 L). The mixture was heated to 80 °C and held at this temperature for 24 hours after which a second charge of potassium cyanide (2.16 kg, 33 mol) was made and heating continued for a further 24 hours. The reaction was allowed to cool to room temperature overnight and then water (30 L) and IPAc (30 L) were added and the layers separated. The aqueous layer was re-extracted with IPAc (30 L) and the combined organics were then washed with 10% aq Νa2CO3 (30 L) and brine (30 L). The combined organics were concentrated to a minimum volume (ca 7 L) and then denatured ethanol (14 L) was added. Concentration to a minimum volume (ca 7 L) afforded a solution of the crude nitrile (2.07 kg, 77% assay yield). In addition, this solution also contains 150 g of the regioisomeric nitrile. Denatured ethanol (30 L) and cone HC1 (4.1 L) were added to an ethanolic solution of the crude nitrile (4.2 kg, 2.07 kg assay, 17.0 mol). Damp 10% palladium on carbon (480 g, 0.1 dry weight equiv) was added and the mixture vigorously stirred under a hydrogen atmosphere (50 psi) for 6 hours. After degassing, the mixture was filtered and then activated carbon (Darco G-60, 480 g) was added and the mixture stirred for 1 hour at room temperature. After filtering to remove the carbon, the solution was concentrated to ca 14 L at which time precipitation of the amine.2HCl occurred. IPAc (20 L) was added dropwise over two hours with stirring and the solid was then isolated by filtration, dried (40 °C ) under vacuum, to afford 2-aminomethyl-3-fluoropyridine.2HCl ϋ (2.37 kg, 70% yield, 98 LCAP). A second crop was obtained by concentrating the filtrate to 10 L and then addition of IPAc (10 L) followed by filtration of the crystalline 2-aminomethyl-3-fluoropyridine.2HCl (430 g, 13% yield, 90 LCAP).
Recrystallization of 2-aminomethyl-3-fluoropyridine.2HCl (11)
2-Aminomethyl-3-fluoropyridine.2HCl 11 (2.0 kg, 10.0 mol, 98 LCAP) was suspended in acetic acid (20 L) under a nitrogen atmosphere with stirring and heated to 100 °C when complete dissolution had taken place. The solution was cooled slowly and precipitation started at 70 °C after which the HC1
in acetic acid (5.0 L of 1.9 M sol) was added slowly. Cooling to room temperature took place overnight after which the solid was collected by filtration and washed with IPAc (15 L), then dried overnight at 40 °C in vacuo to afford the purified amine.2HCl (1.81 kg, 90% recovery) as a crystalline solid. Mp showed slow sublimation from 160 °C onwards.
Proton spectrum in methylene chloride d2 at 250 MHz on Bruker DRX 250. d = doublet, t = triplet, s = singlet, q = quartet.
8.40ppm, dt, 1.2, 4.7 Hz, IH; 7.60ppm, dt, 1.2, 8.5 Hz, IH; 7.41ppm, br q, 4.3 Hz,
IH; 4.28ppm, s, 2H.
Claims (27)
1. A process for preparing 2,2-difluoro-2-(2-pyridyl)-ethan-l-ol, which comprises coupling 2-bromopyridine with ethyl 2-bromo-2,2-difluoroacetate, in the presence of metallic copper and a solvent, to form 2,2-difluoro-2-(2- pyridyl)acetate.
2. A process of Claim 1, wherein the metallic copper is nonactive copper powder, and the solvent is a non-reactive solvent, the reducing agent is a borohydride or aluminium hydride reagent.
3. A process of Claim 2, wherein the nonactive copper powder is copper-bronze, the solvent is dimethyl sulfoxide or dimethylformamide, and the reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium aluminium hydride, and lithium aluminium hydride.
4. A process for preparing 2,2-difluoro-2-(2-pyridyl)-ethan-l-ol which comprises reducing 2,2-difluoro-2-(2-pyridyl)acetate with a reducing agent in the presence of a solvent, to form the 2,2-difluoro-2-(2-pyridyl)-ethan-l-ol.
5. A process of Claim 4, wherein the solvent is an alcohol.
6. A process for preparing 2,2-difluoro-2-(2-pyridyl)ethylamine benzenesulfonate salt which comprises adding trifluoromethanesulfonic anhydride to a solution of 2,2-difluoro-2-(pyridyl)ethanol in acetonitrile, and thereafter adding an ammonium reagent and a solution of benzenesulfonic acid to form 2,2-difluoro-2-(2- pyridyl)ethylamine benzenesulfonate salt.
7. A process of Claim 6, wherein the ammonium reagent is aqueous ammonia.
8. A process for preparing ethyl 2-{(N-(2,2- dimethoxyethyl)carbamoyl Jcarbonylamino) acetate which comprises reacting ethyl glycine hydrochloric acid salt with ethyl oxalyl chloride in the presence of a first non- reactive solvent to form a reaction product, adding 2,2-dimethoxyethylamine to the reaction product to form ethyl 2-{ (N-(2,2-dimethoxyethyl)carbamoyl jcarbonylamino) acetate, and precipitating the ethyl 2-{(N-(2,2- dimethoxyethyl)carbamoyl jcarbonylamino) acetate with a second non-reactive solvent.
9. A process of Claim 8, wherein the first non-reactive solvent is isopropyl acetate and the second non-reactive solvent is heptane.
10. A process for preparing ethyl 2-(2,3-dioxo-l,4-dihydropyrazinyl) acetate which comprises cyclizing ethyl 2-{(N-(2,2- dimethoxyethyl)carbamoyl jcarbonylamino) acetate in the presence of an acid reagent in a solvent.
11. A process of Claim 10, wherein the acid reagent is trifluoroacetic acid and the solvent is acetic acid.
12. A process for preparing ethyl 3-chloropyrazin(lH)-2-one-l-acetate which comprises reacting ethyl 2-(2,3-dioxo-l,4-dihydropyrazinyl)acetate with a chlorinating reagent in the presence of a non-reactive solvent to form ethyl 3- chloropyrazin(lH)-2-one-l-acetate.
13. A process of Claim 12, wherein the chlorinating reagent is selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, a mixture of triphenylphosphine and N- chlorosuccinimide, and a mixture of tetrabutyl ammonium chloride and phosphorous pentoxide, and the non-reactive solvent is selected from the group consisting of isopropyl acetate, 1,2-dichloroethane, toluene, dimethylformamide, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, benzene, propionitrile, acetonitrile and methyl acetate.
14. A process for preparing ethyl 3-(2,2-difluoro-2-(2- pyridylethylamino)pyrazin(lH)-2-one-l-acetate which comprises coupling ethyl 3- chloropyrazin(lH)-2-one-l -acetate with 2,2-difluoro-2-(2-pyridyl)ethylamine benzenesulfonate salt in the presence of a base, a non-reactive solvent, and an iodide, to form ethyl 3-(2,2-difluoro-2-(2-pyridylethylamino)pyrazin(lH)-2-one-l-acetate.
15. A process of Claim 14, wherein the iodide is sodium iodide.
16. A process of Claim 14, wherein the base is N,N- diisopropylethylamine, triethyl amine or tributyl amine, and the non-reactive solvent is acetonitrile
17. A process for preparing 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro- 2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-l-acetamide which comprises coupling
with 2-aminomethyl-3-fluoropyridine dihydrochloric acid salt in the presence of a coupling reagent and a base to form 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2- pyridyl)ethylamino)-6-chloropyrazin-2-one-l-acetamide.
18. A process of Claim 17, wherein the coupling reagent is selected from l-(3-dimethylaminopropyl)-3-ethylcarbdiimide hydrochloride and 1,3- dicyclocarbdiimide.
19. A process of Claim 17, wherein the base is potassium hydroxide.
20. A compound having the formula
wherein R is Ci-4 alkyl.
21. A compound of Claim 20 wherein R is -CH2CH3.
22. A process for recrystallizing 2-aminomethyl-3-fluoropyridine dihydrochloride which comprises suspending 2-aminomethyl-3-fluoropyridine dihydrochloride in acetic acid, heating to dissolve the 2-aminomethyl-3- fluoropyridine dihydrochloride into a solution, and precipitating the 2-aminomethyl-3- fluoropyridine dihydrochloride from the solution.
23. A process for preparing 2-{3-[(2,2-difluoro-2-(2- pyridyl)ethyl)amino]-6-chloro-2-oxohydro-pyrazinyl jacetate which comprises chlorinating ethyl 3-(2,2-difluoro-2-(2-pyridylethylamino)pyrazin(lH)-2-one-l- acetate with N-chlorosuccinimide or 1,3 dichloro-5,5-dimethylhydantoin in the presence of a non-reactive solvent.
24. A process of Claim 23 wherein the non-reactive solvent is acetonitrile.
25. A process for preparing 2-cyano-3-fluoropyridine comprising adding chlorotrimethylsilane to a mixture comprising 3 -fluoropyridine N-oxide and potassium cyanide to form 2-cyano-3-fluoropyridine.
26. A process for preparing ethyl 2-(2,3-dioxo-l,4- dihydropyrazinyl)acetate which comprises preparing ethyl 2-{(N-(2,2- dimethoxyethyl)carbamoyl jcarbonylamino) acetate by reacting ethyl glycine hydrochloric acid salt with ethyl oxalyl chloride in the presence of a first non-reactive solvent to form a first reaction product, adding 2,2-dimethoxyethylamine to the first reaction product to form a second reaction product comprising ethyl 2-{(N-(2,2- dimethoxyethyl)carbamoyl jcarbonylamino) acetate, and cyclizing ethyl 2-{(N-(2,2- dimethoxyethyl)carbamoyl jcarbonylamino) acetate in the presence of an acid reagent and a second solvent to form ethyl 2-(2,3-dioxo-l,4-dihydropyrazinyl)acetate.
27. A process of Claim 26, wherein the first non-reactive solvent is isopropyl acetate, the acid reagent is trifluoroacetic acid and the second solvent is acetic acid.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0029728 | 2000-12-06 | ||
GB0029728A GB0029728D0 (en) | 2000-12-06 | 2000-12-06 | Process for making a thrombin inhibitor |
GB0105911 | 2001-03-09 | ||
GB0105911A GB0105911D0 (en) | 2001-03-09 | 2001-03-09 | Process for making a thrombon inhibitor |
PCT/US2001/047439 WO2002046160A2 (en) | 2000-12-06 | 2001-12-04 | Process for making a thrombin inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2002232533A1 true AU2002232533A1 (en) | 2002-06-18 |
Family
ID=26245385
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2002232533A Abandoned AU2002232533A1 (en) | 2000-12-06 | 2001-12-04 | Process for making a thrombin inhibitor |
Country Status (6)
Country | Link |
---|---|
US (1) | US20020103379A1 (en) |
EP (1) | EP1341784A2 (en) |
JP (1) | JP2004518643A (en) |
AU (1) | AU2002232533A1 (en) |
CA (1) | CA2430842A1 (en) |
WO (1) | WO2002046160A2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2778922A1 (en) * | 2009-11-03 | 2011-05-12 | Diakron Pharmaceuticals, Inc. | Process for the preparation of pyrazinone thrombin inhibitor and its intermediates |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001514227A (en) * | 1997-09-05 | 2001-09-11 | メルク エンド カムパニー インコーポレーテッド | Pyrazinone thrombin inhibitors |
EP1124822A4 (en) * | 1998-10-30 | 2002-04-03 | Merck & Co Inc | Thrombin inhibitors |
-
2001
- 2001-12-04 AU AU2002232533A patent/AU2002232533A1/en not_active Abandoned
- 2001-12-04 WO PCT/US2001/047439 patent/WO2002046160A2/en not_active Application Discontinuation
- 2001-12-04 CA CA002430842A patent/CA2430842A1/en not_active Abandoned
- 2001-12-04 JP JP2002547899A patent/JP2004518643A/en not_active Withdrawn
- 2001-12-04 EP EP01992059A patent/EP1341784A2/en not_active Withdrawn
- 2001-12-06 US US10/013,063 patent/US20020103379A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
CA2430842A1 (en) | 2002-06-13 |
JP2004518643A (en) | 2004-06-24 |
WO2002046160A3 (en) | 2003-03-06 |
US20020103379A1 (en) | 2002-08-01 |
EP1341784A2 (en) | 2003-09-10 |
WO2002046160A2 (en) | 2002-06-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5766204B2 (en) | Method for synthesizing factor Xa inhibitor | |
US6376499B1 (en) | Thrombin inhibitors | |
EP0900207A1 (en) | Pyrazinone thrombin inhibitors | |
WO1996018616A1 (en) | Substituted 2-aminopyridines as inhibitors of nitric oxide synthase | |
EP1082324A1 (en) | Imidazopyridine thrombin inhibitors | |
EP1267876A1 (en) | Thrombin inhibitors | |
JP2004502757A (en) | Pyridoxine and pyridoxal analogs: Cardiovascular therapeutics | |
JP3539926B2 (en) | Antiviral pyrimidinedione derivatives and methods for their production | |
AU2044401A (en) | Pyrazinone thrombin inhibitors | |
AU2002232533A1 (en) | Process for making a thrombin inhibitor | |
US20030158218A1 (en) | Thrombin inhibitors | |
EP1326838B1 (en) | Novel crystalline forms of a factor xa inhibitor | |
US6239132B1 (en) | Thrombin inhibitors | |
US6462050B1 (en) | Thrombin inhibitors | |
JPH10114744A (en) | Aminoguanidinehydrazone derivative, and its production and pharmaceutical preparation | |
AU2002211425A1 (en) | Novel crystalline forms of a factor XA inhibitor | |
WO1999015169A1 (en) | Thrombin inhibitors | |
EP1039907A1 (en) | Thrombin inhibitors | |
GB2343180A (en) | Process for making pyrazinone compounds used as thrombin inhibitors | |
EP1189618A1 (en) | Thrombin inhibitors | |
EP1526131A1 (en) | Aminoalkyl-pyrazinones and -pyridones as thrombin inhibitors | |
AU746024B2 (en) | Pyrazinone thrombin inhibitors | |
JP2021514362A (en) | Receptor inhibitor, pharmaceutical composition containing the inhibitor and its use | |
EP1655296A1 (en) | Thrombin inhibitors | |
JPH0477745B2 (en) |