FI107606B - Menetelmä valmistaa farmaseuttisesti arvokkaita 1-, 3-, 5-substituoituja pyrrolidin-2-oneja - Google Patents
Menetelmä valmistaa farmaseuttisesti arvokkaita 1-, 3-, 5-substituoituja pyrrolidin-2-oneja Download PDFInfo
- Publication number
- FI107606B FI107606B FI915136A FI915136A FI107606B FI 107606 B FI107606 B FI 107606B FI 915136 A FI915136 A FI 915136A FI 915136 A FI915136 A FI 915136A FI 107606 B FI107606 B FI 107606B
- Authority
- FI
- Finland
- Prior art keywords
- group
- pyrrolidinone
- methyl
- oxymethyl
- biphenylyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 13
- 230000008569 process Effects 0.000 title claims abstract description 7
- -1 5-substituted pyrrolidin-2-ones Chemical class 0.000 title claims description 331
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 134
- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 239000000460 chlorine Substances 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 25
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 13
- 230000003647 oxidation Effects 0.000 claims description 13
- 238000007254 oxidation reaction Methods 0.000 claims description 13
- 239000011541 reaction mixture Substances 0.000 claims description 12
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 238000003776 cleavage reaction Methods 0.000 claims description 7
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 230000007017 scission Effects 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 238000001149 thermolysis Methods 0.000 claims description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- IKZACQMAVUIGPY-HOTGVXAUSA-N fradafiban Chemical compound C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1NC(=O)[C@H](CC(O)=O)C1 IKZACQMAVUIGPY-HOTGVXAUSA-N 0.000 claims description 4
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 4
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 150000001409 amidines Chemical class 0.000 claims description 3
- 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- PGCFXITVMNNKON-ROUUACIJSA-N lefradafiban Chemical compound N1C(=O)[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(=N)NC(=O)OC)C=C1 PGCFXITVMNNKON-ROUUACIJSA-N 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000002071 phenylalkoxy group Chemical group 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 2
- 125000000320 amidine group Chemical group 0.000 claims 1
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims 1
- 230000009257 reactivity Effects 0.000 claims 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 150000007524 organic acids Chemical class 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 230000002776 aggregation Effects 0.000 abstract description 2
- 238000004220 aggregation Methods 0.000 abstract description 2
- 150000007522 mineralic acids Chemical class 0.000 abstract description 2
- 235000005985 organic acids Nutrition 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 762
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 588
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 561
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 379
- 239000000741 silica gel Substances 0.000 description 365
- 229910002027 silica gel Inorganic materials 0.000 description 365
- 235000019439 ethyl acetate Nutrition 0.000 description 187
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 115
- 238000002844 melting Methods 0.000 description 115
- 230000008018 melting Effects 0.000 description 115
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 105
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 100
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 99
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 98
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 96
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 86
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 81
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 55
- 239000000243 solution Substances 0.000 description 49
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- 235000002639 sodium chloride Nutrition 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 239000002904 solvent Substances 0.000 description 38
- 239000012071 phase Substances 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 30
- 230000002441 reversible effect Effects 0.000 description 30
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 29
- 229960000583 acetic acid Drugs 0.000 description 27
- 239000011780 sodium chloride Substances 0.000 description 27
- 238000003756 stirring Methods 0.000 description 27
- 239000012362 glacial acetic acid Substances 0.000 description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 18
- 238000001819 mass spectrum Methods 0.000 description 17
- WPHGSKGZRAQSGP-UHFFFAOYSA-N methylenecyclohexane Natural products C1CCCC2CC21 WPHGSKGZRAQSGP-UHFFFAOYSA-N 0.000 description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- DQRFCVHLNUNVPL-UHFFFAOYSA-N 2h-1,3-oxazol-5-one Chemical compound O=C1OCN=C1 DQRFCVHLNUNVPL-UHFFFAOYSA-N 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 7
- 229910021529 ammonia Inorganic materials 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 229940012952 fibrinogen Drugs 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 108010049003 Fibrinogen Proteins 0.000 description 6
- 102000008946 Fibrinogen Human genes 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- YIECBEODHQJXSX-UHFFFAOYSA-N Cl.COC(=O)CN1CCCC1=O Chemical compound Cl.COC(=O)CN1CCCC1=O YIECBEODHQJXSX-UHFFFAOYSA-N 0.000 description 5
- 102000008186 Collagen Human genes 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 125000004344 phenylpropyl group Chemical group 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- FQSSRLVFPQIRJK-QFIPXVFZSA-N (5s)-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound N1C(=O)CC[C@H]1COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 FQSSRLVFPQIRJK-QFIPXVFZSA-N 0.000 description 4
- 125000006516 2-(benzyloxy)ethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- ZRMIETZFPZGBEB-UHFFFAOYSA-N 4-(4-hydroxyphenyl)benzonitrile Chemical group C1=CC(O)=CC=C1C1=CC=C(C#N)C=C1 ZRMIETZFPZGBEB-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000001099 ammonium carbonate Substances 0.000 description 4
- 235000012501 ammonium carbonate Nutrition 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 150000007530 organic bases Chemical group 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- JGPIWNNFLKDTSR-UHFFFAOYSA-N 2-(2-oxopyrrolidin-1-yl)acetic acid Chemical compound OC(=O)CN1CCCC1=O JGPIWNNFLKDTSR-UHFFFAOYSA-N 0.000 description 3
- YTQOLGKWDFKZES-IRXDYDNUSA-N 2-[(3s,5s)-5-[[4-[4-(aminomethyl)-2-methylphenyl]phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound CC1=CC(CN)=CC=C1C(C=C1)=CC=C1OC[C@H]1NC(=O)[C@H](CC(O)=O)C1 YTQOLGKWDFKZES-IRXDYDNUSA-N 0.000 description 3
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 239000005662 Paraffin oil Substances 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- 238000005345 coagulation Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical compound COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 229920000058 polyacrylate Polymers 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229960003975 potassium Drugs 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- CGFYJMQPWQTZQA-HKBQPEDESA-N (5s)-1-(3-phenylpropyl)-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C([C@@H]1CCC(N1CCCC=1C=CC=CC=1)=O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CGFYJMQPWQTZQA-HKBQPEDESA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- YHIIJNLSGULWAA-UHFFFAOYSA-N 1,4-thiazinane 1-oxide Chemical compound O=S1CCNCC1 YHIIJNLSGULWAA-UHFFFAOYSA-N 0.000 description 2
- BKAJUOZPTJKINN-UHFFFAOYSA-N 1-(3-phenylpropyl)pyrrolidin-2-one Chemical compound O=C1CCCN1CCCC1=CC=CC=C1 BKAJUOZPTJKINN-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ORLHWHOFZHHAIB-GOTSBHOMSA-N 2-[(3s,5s)-1-[2-(benzenesulfonamido)ethyl]-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1N(CCNS(=O)(=O)C=2C=CC=CC=2)C(=O)[C@H](CC(O)=O)C1 ORLHWHOFZHHAIB-GOTSBHOMSA-N 0.000 description 2
- FOCHURRHVXWYNP-UIOOFZCWSA-N 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)O)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 FOCHURRHVXWYNP-UIOOFZCWSA-N 0.000 description 2
- XTOLNXIUFOUMOU-AHWVRZQESA-N 2-[(3s,5s)-5-[[[3-(3-aminophenyl)benzoyl]amino]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetic acid Chemical compound NC1=CC=CC(C=2C=C(C=CC=2)C(=O)NC[C@H]2N(C(=O)[C@H](CC(O)=O)C2)CCCC=2C=CC=CC=2)=C1 XTOLNXIUFOUMOU-AHWVRZQESA-N 0.000 description 2
- XFCDLTAEHVHQMW-UHFFFAOYSA-N 2-[2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetic acid hydrate Chemical compound O.C(=O)(O)CC1C(N(CC1)CCCC1=CC=CC=C1)=O XFCDLTAEHVHQMW-UHFFFAOYSA-N 0.000 description 2
- YOVZFHWMFCKXPE-UHFFFAOYSA-N 2-chloro-4-(4-hydroxyphenyl)benzamide Chemical group C1=C(Cl)C(C(=O)N)=CC=C1C1=CC=C(O)C=C1 YOVZFHWMFCKXPE-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 2
- XMZQWZJMTBCUFT-UHFFFAOYSA-N 3-bromopropylbenzene Chemical compound BrCCCC1=CC=CC=C1 XMZQWZJMTBCUFT-UHFFFAOYSA-N 0.000 description 2
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 2
- BKYIMUSAVMSMGK-UHFFFAOYSA-N 4,5-dihydropyridazine Chemical compound C1CC=NN=C1 BKYIMUSAVMSMGK-UHFFFAOYSA-N 0.000 description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 206010053567 Coagulopathies Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- FCLZCOCSZQNREK-UHFFFAOYSA-N Pyrrolidine, hydrochloride Chemical compound Cl.C1CCNC1 FCLZCOCSZQNREK-UHFFFAOYSA-N 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000004647 alkyl sulfenyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 2
- 230000035602 clotting Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- CVTXXERYNNQITJ-UIOOFZCWSA-N methyl 2-[(3s,5s)-5-[[2-amino-4-(4-cyanophenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C(=C1)N)=CC=C1C1=CC=C(C#N)C=C1 CVTXXERYNNQITJ-UIOOFZCWSA-N 0.000 description 2
- XTRCQYBLRCTFEV-GUTACTQSSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-(2-carbamoylphenyl)-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1C=1C(=CC=CC=1)C(N)=O)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 XTRCQYBLRCTFEV-GUTACTQSSA-N 0.000 description 2
- UMUWWKDCBMTCLY-TUYUPMGOSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[3-(methanesulfonamido)phenyl]-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1C=1C=C(NS(C)(=O)=O)C=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 UMUWWKDCBMTCLY-TUYUPMGOSA-N 0.000 description 2
- XNTVAUUEOXENRW-UHFFFAOYSA-N methyl 2-[2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound O=C1C(CC(=O)OC)CCN1CCCC1=CC=CC=C1 XNTVAUUEOXENRW-UHFFFAOYSA-N 0.000 description 2
- ABSIURIPZLLJLF-UHFFFAOYSA-N methyl 2-[2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate hydrochloride Chemical compound Cl.O=C1C(CC(=O)OC)CCN1CCCC1=CC=CC=C1 ABSIURIPZLLJLF-UHFFFAOYSA-N 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- KIANWQPBIVTBHR-UIOOFZCWSA-N tert-butyl 2-[(3s,5s)-2-oxo-5-[[4-[4-[(z)-n'-phenylmethoxycarbonylcarbamimidoyl]phenyl]phenoxy]methyl]pyrrolidin-3-yl]acetate Chemical compound N1C(=O)[C@H](CC(=O)OC(C)(C)C)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(\N)=N\C(=O)OCC=2C=CC=CC=2)C=C1 KIANWQPBIVTBHR-UIOOFZCWSA-N 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- ZTWIEIFKPFJRLV-UHFFFAOYSA-K trichlororuthenium;trihydrate Chemical compound O.O.O.Cl[Ru](Cl)Cl ZTWIEIFKPFJRLV-UHFFFAOYSA-K 0.000 description 2
- 125000000026 trimethylsilyl group Chemical class [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 229940038773 trisodium citrate Drugs 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- CGFYJMQPWQTZQA-WJOKGBTCSA-N (5r)-1-(3-phenylpropyl)-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C([C@H]1CCC(N1CCCC=1C=CC=CC=1)=O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CGFYJMQPWQTZQA-WJOKGBTCSA-N 0.000 description 1
- ZFBHNKRVTJSQCU-SANMLTNESA-N (5s)-1-(2-methylpropyl)-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C1CC(=O)N(CC(C)C)[C@@H]1COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ZFBHNKRVTJSQCU-SANMLTNESA-N 0.000 description 1
- ZANXDOSESYLKIC-PMERELPUSA-N (5s)-1-(2-phenylethyl)-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C([C@@H]1CCC(N1CCC=1C=CC=CC=1)=O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ZANXDOSESYLKIC-PMERELPUSA-N 0.000 description 1
- VZCBAZAXFYAHRI-HKBQPEDESA-N (5s)-1-(3-cyclohexylpropyl)-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C([C@@H]1CCC(N1CCCC1CCCCC1)=O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 VZCBAZAXFYAHRI-HKBQPEDESA-N 0.000 description 1
- KQAZBARFLGZPCM-HKBQPEDESA-N (5s)-1-(4-phenoxybutyl)-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C([C@@H]1CCC(N1CCCCOC=1C=CC=CC=1)=O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KQAZBARFLGZPCM-HKBQPEDESA-N 0.000 description 1
- TXAHHGKBPFFYOY-YTTGMZPUSA-N (5s)-1-(4-phenylbutyl)-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C([C@@H]1CCC(N1CCCCC=1C=CC=CC=1)=O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 TXAHHGKBPFFYOY-YTTGMZPUSA-N 0.000 description 1
- OTKMSXZXLYPVCY-LJAQVGFWSA-N (5s)-1-[(4-methoxyphenyl)methyl]-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C1=CC(OC)=CC=C1CN1C(=O)CC[C@H]1COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 OTKMSXZXLYPVCY-LJAQVGFWSA-N 0.000 description 1
- KQWPPXCPZPFNEY-QNGWXLTQSA-N (5s)-1-[3-(4-phenylmethoxyphenyl)propyl]-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C([C@@H]1CCC(N1CCCC=1C=CC(OCC=2C=CC=CC=2)=CC=1)=O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KQWPPXCPZPFNEY-QNGWXLTQSA-N 0.000 description 1
- WDOUZYOKKIKCKX-LJAQVGFWSA-N (5s)-1-benzyl-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C([C@@H]1CCC(N1CC=1C=CC=CC=1)=O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WDOUZYOKKIKCKX-LJAQVGFWSA-N 0.000 description 1
- CUHFGNCQUYBZDA-QHCPKHFHSA-N (5s)-1-methyl-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C1CC(=O)N(C)[C@@H]1COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CUHFGNCQUYBZDA-QHCPKHFHSA-N 0.000 description 1
- URKMZDLSQLTWPY-NDEPHWFRSA-N (5s)-1-phenyl-5-(trityloxymethyl)pyrrolidin-2-one Chemical compound C([C@@H]1CCC(N1C=1C=CC=CC=1)=O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 URKMZDLSQLTWPY-NDEPHWFRSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BCNBMSZKALBQEF-UHFFFAOYSA-N 1,3-dimethylpyrrolidin-2-one Chemical compound CC1CCN(C)C1=O BCNBMSZKALBQEF-UHFFFAOYSA-N 0.000 description 1
- UPMSOPUSVQPZKN-UHFFFAOYSA-N 1-(2-oxo-2-piperidin-1-ylethyl)pyrrolidin-2-one Chemical compound C1CCCCN1C(=O)CN1CCCC1=O UPMSOPUSVQPZKN-UHFFFAOYSA-N 0.000 description 1
- NKMOWVIDVYVSTJ-UHFFFAOYSA-N 1-(3-phenylpropyl)pyrrolidin-2-one hydrate Chemical compound O.O=C1CCCN1CCCC1=CC=CC=C1 NKMOWVIDVYVSTJ-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- UAGMFWLBFBJCHX-UHFFFAOYSA-N 1-methylpyrrolidin-2-one;dihydrate Chemical compound O.O.CN1CCCC1=O UAGMFWLBFBJCHX-UHFFFAOYSA-N 0.000 description 1
- 229940044613 1-propanol Drugs 0.000 description 1
- LNSCNEJNLACZPA-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(2-methylphenyl)butanedioic acid Chemical compound CC1=CC=CC=C1C(O)(C(O)=O)C(O)(C(O)=O)C1=CC=CC=C1C LNSCNEJNLACZPA-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- SRQAJMUHZROVHW-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)ethanol Chemical compound COC1=CC=C(CCO)C=C1OC SRQAJMUHZROVHW-UHFFFAOYSA-N 0.000 description 1
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- KVYFVGUISKBOTH-XCZPVHLTSA-N 2-[(3S,5S)-1-[3-(4-tert-butylphenyl)propyl]-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C(N)(=N)C1=CC=C(C=C1)C1=CC=C(C=C1)OC[C@@H]1C[C@H](C(N1CCCC1=CC=C(C=C1)C(C)(C)C)=O)CC(=O)O KVYFVGUISKBOTH-XCZPVHLTSA-N 0.000 description 1
- FKGIVPKHUJPAND-DQEYMECFSA-N 2-[(3S,5S)-5-[[4-(4-carbamimidoyl-2-methylphenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetic acid Chemical compound C(N)(=N)C1=CC(=C(C=C1)C1=CC=C(C=C1)OC[C@@H]1C[C@H](C(N1CCCC1=CC=CC=C1)=O)CC(=O)O)C FKGIVPKHUJPAND-DQEYMECFSA-N 0.000 description 1
- PXDLETANBWMQBO-HLRBRJAUSA-N 2-[(3S,5S)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[2-(dimethylamino)-2-oxoethyl]-2-oxopyrrolidin-3-yl]acetic acid hydrochloride Chemical compound CN(C)C(=O)CN1[C@@H](C[C@H](C1=O)CC(=O)O)COC2=CC=C(C=C2)C3=CC=C(C=C3)C(=N)N.Cl PXDLETANBWMQBO-HLRBRJAUSA-N 0.000 description 1
- IKZACQMAVUIGPY-HZPDHXFCSA-N 2-[(3r,5r)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@@H]1NC(=O)[C@@H](CC(O)=O)C1 IKZACQMAVUIGPY-HZPDHXFCSA-N 0.000 description 1
- CKEKZPJKVZXTBQ-SJORKVTESA-N 2-[(3r,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound N1C(=O)[C@@H](CC(=O)O)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C#N)C=C1 CKEKZPJKVZXTBQ-SJORKVTESA-N 0.000 description 1
- OFYRXZLWNRBXSD-GOTSBHOMSA-N 2-[(3s,5s)-1-[2-(benzenesulfonyl)ethyl]-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1N(CCS(=O)(=O)C=2C=CC=CC=2)C(=O)[C@H](CC(O)=O)C1 OFYRXZLWNRBXSD-GOTSBHOMSA-N 0.000 description 1
- SOPXQZOKRNLRRK-OUTSHDOLSA-N 2-[(3s,5s)-2-oxo-1-phenyl-5-(trityloxymethyl)pyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]1C[C@H](C(N1C=1C=CC=CC=1)=O)CC(=O)O)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 SOPXQZOKRNLRRK-OUTSHDOLSA-N 0.000 description 1
- WRTAADRUJXTHCV-GOTSBHOMSA-N 2-[(3s,5s)-2-oxo-5-[[4-[4-[(e)-n'-phenylmethoxycarbonylcarbamimidoyl]phenyl]phenoxy]methyl]pyrrolidin-3-yl]acetic acid Chemical compound N1C(=O)[C@H](CC(=O)O)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(=N)NC(=O)OCC=2C=CC=CC=2)C=C1 WRTAADRUJXTHCV-GOTSBHOMSA-N 0.000 description 1
- WBKTYOAXRYQKGF-VMPREFPWSA-N 2-[(3s,5s)-5-[[4-(4-aminobutyl)phenoxy]methyl]-2-oxo-1-[3-(4-phenylmethoxyphenyl)propyl]pyrrolidin-3-yl]acetic acid Chemical compound C1=CC(CCCCN)=CC=C1OC[C@H]1N(CCCC=2C=CC(OCC=3C=CC=CC=3)=CC=2)C(=O)[C@H](CC(O)=O)C1 WBKTYOAXRYQKGF-VMPREFPWSA-N 0.000 description 1
- HOAJNIOPQAZKRL-KBPBESRZSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoyl-3-chlorophenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1=C(Cl)C(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1NC(=O)[C@H](CC(O)=O)C1 HOAJNIOPQAZKRL-KBPBESRZSA-N 0.000 description 1
- GTIGTRCOFKFRGW-SFTDATJTSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-(2-morpholin-4-yl-2-oxoethyl)-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1N(CC(=O)N2CCOCC2)C(=O)[C@H](CC(O)=O)C1 GTIGTRCOFKFRGW-SFTDATJTSA-N 0.000 description 1
- CXEIFEYBZHAISU-PMACEKPBSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-(3-methylsulfonylpropyl)-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1[C@@H](CC(O)=O)C(=O)N(CCCS(=O)(=O)C)[C@@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 CXEIFEYBZHAISU-PMACEKPBSA-N 0.000 description 1
- FLOIZQQSHBNXOM-IRXDYDNUSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-(carboxymethyl)-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1N(CC(O)=O)C(=O)[C@H](CC(O)=O)C1 FLOIZQQSHBNXOM-IRXDYDNUSA-N 0.000 description 1
- RPZKIARXGJOAHX-GOTSBHOMSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[(4-methoxyphenyl)methyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1=CC(OC)=CC=C1CN1C(=O)[C@H](CC(O)=O)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 RPZKIARXGJOAHX-GOTSBHOMSA-N 0.000 description 1
- GIRRMKHEQLYQPO-XYOGLKKJSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[3-(2,4-dichlorophenyl)propyl]-2-oxopyrrolidin-3-yl]acetic acid;hydrate Chemical compound O.C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1N(CCCC=2C(=CC(Cl)=CC=2)Cl)C(=O)[C@H](CC(O)=O)C1 GIRRMKHEQLYQPO-XYOGLKKJSA-N 0.000 description 1
- SMEHMVSDKOBDFW-DQEYMECFSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[3-(3,4-dimethoxyphenyl)propyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1=C(OC)C(OC)=CC=C1CCCN1C(=O)[C@H](CC(O)=O)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 SMEHMVSDKOBDFW-DQEYMECFSA-N 0.000 description 1
- XOALFSTVVRQZQG-PNHSAAKESA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[3-(4-hexoxyphenyl)propyl]-2-oxopyrrolidin-3-yl]acetic acid;hydrate Chemical compound O.C1=CC(OCCCCCC)=CC=C1CCCN1C(=O)[C@H](CC(O)=O)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 XOALFSTVVRQZQG-PNHSAAKESA-N 0.000 description 1
- PDJHUIYCYOPPJU-UPVQGACJSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[3-(ethylcarbamoyl)phenyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound CCNC(=O)C1=CC=CC(N2C([C@H](CC(O)=O)C[C@H]2COC=2C=CC(=CC=2)C=2C=CC(=CC=2)C(N)=N)=O)=C1 PDJHUIYCYOPPJU-UPVQGACJSA-N 0.000 description 1
- AXLXBRQLGUDNNH-UPVQGACJSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[4-(ethylcarbamoyl)phenyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1=CC(C(=O)NCC)=CC=C1N1C(=O)[C@H](CC(O)=O)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 AXLXBRQLGUDNNH-UPVQGACJSA-N 0.000 description 1
- WPYAKRHWSXYNPP-IRXDYDNUSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-methyl-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1[C@@H](CC(O)=O)C(=O)N(C)[C@@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 WPYAKRHWSXYNPP-IRXDYDNUSA-N 0.000 description 1
- IFADTVPQYSGHMI-GOTSBHOMSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxo-1-(2-phenylsulfanylethyl)pyrrolidin-3-yl]acetic acid Chemical compound C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1N(CCSC=2C=CC=CC=2)C(=O)[C@H](CC(O)=O)C1 IFADTVPQYSGHMI-GOTSBHOMSA-N 0.000 description 1
- PMYFDGOSGGCNSQ-VMPREFPWSA-N 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxo-1-[(4-phenylphenyl)methyl]pyrrolidin-3-yl]acetic acid Chemical compound C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1N(CC=2C=CC(=CC=2)C=2C=CC=CC=2)C(=O)[C@H](CC(O)=O)C1 PMYFDGOSGGCNSQ-VMPREFPWSA-N 0.000 description 1
- GLLVUOBSTPMOTI-PMACEKPBSA-N 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-1-[2-(dimethylamino)-2-oxoethyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1[C@@H](CC(O)=O)C(=O)N(CC(=O)N(C)C)[C@@H]1COC1=CC=C(C=2C=CC(=CC=2)C#N)C=C1 GLLVUOBSTPMOTI-PMACEKPBSA-N 0.000 description 1
- JBNGCCRBXREQTR-PMACEKPBSA-N 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-1-[2-(ethylamino)-2-oxoethyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound C1[C@@H](CC(O)=O)C(=O)N(CC(=O)NCC)[C@@H]1COC1=CC=C(C=2C=CC(=CC=2)C#N)C=C1 JBNGCCRBXREQTR-PMACEKPBSA-N 0.000 description 1
- PKQIKFVQPVLSMN-ROUUACIJSA-N 2-[(3s,5s)-5-[[4-[4-(aminomethyl)phenyl]-2,3-dimethylphenoxy]methyl]-2-oxopyrrolidin-3-yl]acetic acid Chemical compound CC1=C(C)C(C=2C=CC(CN)=CC=2)=CC=C1OC[C@@H]1C[C@@H](CC(O)=O)C(=O)N1 PKQIKFVQPVLSMN-ROUUACIJSA-N 0.000 description 1
- DPSKTNZVRYNRMK-UIOOFZCWSA-N 2-[(3s,5s)-5-[[4-[4-[(diaminomethylideneamino)methyl]phenyl]phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetic acid Chemical compound C1=CC(CNC(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1N(CCCC=2C=CC=CC=2)C(=O)[C@H](CC(O)=O)C1 DPSKTNZVRYNRMK-UIOOFZCWSA-N 0.000 description 1
- YLMYTHUFSSFEBK-AHWVRZQESA-N 2-[(3s,5s)-5-[[[3-[3-(diaminomethylideneamino)phenyl]benzoyl]amino]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetic acid Chemical compound NC(=N)NC1=CC=CC(C=2C=C(C=CC=2)C(=O)NC[C@H]2N(C(=O)[C@H](CC(O)=O)C2)CCCC=2C=CC=CC=2)=C1 YLMYTHUFSSFEBK-AHWVRZQESA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- BUBBUOUVALIEDT-UHFFFAOYSA-N 2-hydroxy-n,n-di(propan-2-yl)acetamide Chemical compound CC(C)N(C(C)C)C(=O)CO BUBBUOUVALIEDT-UHFFFAOYSA-N 0.000 description 1
- JNQVLKWNKVMFBN-UHFFFAOYSA-N 2-hydroxy-n,n-dimethylacetamide Chemical compound CN(C)C(=O)CO JNQVLKWNKVMFBN-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- GAZRNXIMWKZADY-UHFFFAOYSA-N 3,5-dimethylpyrazole-1-carboximidamide Chemical compound CC=1C=C(C)N(C(N)=N)N=1 GAZRNXIMWKZADY-UHFFFAOYSA-N 0.000 description 1
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XOGXLUAMJUQURP-UHFFFAOYSA-N 3-hydroxy-2h-1,3-benzothiazole Chemical compound C1=CC=C2N(O)CSC2=C1 XOGXLUAMJUQURP-UHFFFAOYSA-N 0.000 description 1
- LXPHILJLRBZZLC-DQEYMECFSA-N 3-phenylpropyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1NC(=O)[C@H](CC(=O)OCCCC=2C=CC=CC=2)C1 LXPHILJLRBZZLC-DQEYMECFSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- PYIUGHJSIAOAPS-UHFFFAOYSA-N 4-(3-bromo-4-hydroxyphenyl)benzonitrile Chemical group C1=C(Br)C(O)=CC=C1C1=CC=C(C#N)C=C1 PYIUGHJSIAOAPS-UHFFFAOYSA-N 0.000 description 1
- QHNXPYROGGWQDV-UHFFFAOYSA-N 4-(3-fluoro-4-hydroxyphenyl)benzonitrile Chemical group C1=C(F)C(O)=CC=C1C1=CC=C(C#N)C=C1 QHNXPYROGGWQDV-UHFFFAOYSA-N 0.000 description 1
- PMSVMKWKALYGOQ-UHFFFAOYSA-N 4-(4-hydroxy-2,3-dimethylphenyl)benzonitrile Chemical group C1=C(O)C(C)=C(C)C(C=2C=CC(=CC=2)C#N)=C1 PMSVMKWKALYGOQ-UHFFFAOYSA-N 0.000 description 1
- YAKUGSKOQDVOIJ-UHFFFAOYSA-N 4-(4-hydroxy-3-methylsulfanylphenyl)benzonitrile Chemical group C1=C(O)C(SC)=CC(C=2C=CC(=CC=2)C#N)=C1 YAKUGSKOQDVOIJ-UHFFFAOYSA-N 0.000 description 1
- YSEMOGXVLHWJLR-UHFFFAOYSA-N 4-(4-hydroxy-3-nitrophenyl)benzonitrile Chemical group C1=C([N+]([O-])=O)C(O)=CC=C1C1=CC=C(C#N)C=C1 YSEMOGXVLHWJLR-UHFFFAOYSA-N 0.000 description 1
- KVBAHALKLZAEMT-UHFFFAOYSA-N 4-(4-hydroxyphenyl)-3-methylbenzonitrile Chemical group CC1=CC(C#N)=CC=C1C1=CC=C(O)C=C1 KVBAHALKLZAEMT-UHFFFAOYSA-N 0.000 description 1
- NOGXHFLRPIQOOJ-VIZCGCQYSA-N 4-[(3r,5s)-1-(2-methylpropyl)-2-oxo-5-(trityloxymethyl)pyrrolidin-3-yl]butanenitrile Chemical compound C1[C@@H](CCCC#N)C(=O)N(CC(C)C)[C@@H]1COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NOGXHFLRPIQOOJ-VIZCGCQYSA-N 0.000 description 1
- NBHFTGONEVFVAO-NEPJUHHUSA-N 4-[(3r,5s)-5-(hydroxymethyl)-1-(2-methylpropyl)-2-oxopyrrolidin-3-yl]butanenitrile Chemical compound CC(C)CN1[C@H](CO)C[C@@H](CCCC#N)C1=O NBHFTGONEVFVAO-NEPJUHHUSA-N 0.000 description 1
- AXXGFTZUNJFSMB-BDAKNGLRSA-N 4-[(3r,5s)-5-(hydroxymethyl)-1-methyl-2-oxopyrrolidin-3-yl]butanenitrile Chemical compound CN1[C@H](CO)C[C@@H](CCCC#N)C1=O AXXGFTZUNJFSMB-BDAKNGLRSA-N 0.000 description 1
- JEGCOEPCAPNPLL-UHFFFAOYSA-N 4-[4-[(2-oxopyrrolidin-1-yl)methoxy]phenyl]benzonitrile Chemical compound C(#N)C1=CC=C(C=C1)C1=CC=C(C=C1)OCN1C(CCC1)=O JEGCOEPCAPNPLL-UHFFFAOYSA-N 0.000 description 1
- YZPGQMJFRMRVGM-DQEYMECFSA-N 4-[4-[[(2s,4s)-4-(2-amino-2-oxoethyl)-5-oxo-1-(3-phenylpropyl)pyrrolidin-2-yl]methoxy]phenyl]benzamide Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)N)OC(C=C1)=CC=C1C1=CC=C(C(N)=O)C=C1 YZPGQMJFRMRVGM-DQEYMECFSA-N 0.000 description 1
- HBKGHUUHOLQCPE-UHFFFAOYSA-N 4-[4-hydroxy-3-(trifluoromethyl)phenyl]benzonitrile Chemical group C1=C(C(F)(F)F)C(O)=CC=C1C1=CC=C(C#N)C=C1 HBKGHUUHOLQCPE-UHFFFAOYSA-N 0.000 description 1
- XPBQQAHIVODAIC-UHFFFAOYSA-N 4-bromobutylbenzene Chemical compound BrCCCCC1=CC=CC=C1 XPBQQAHIVODAIC-UHFFFAOYSA-N 0.000 description 1
- HALXOXQZONRCAB-UHFFFAOYSA-N 4-iodobutanoic acid Chemical compound OC(=O)CCCI HALXOXQZONRCAB-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- HOBJEFOCIRXQKH-UHFFFAOYSA-N 5-(hydroxymethyl)pyrrolidin-2-one Chemical compound OCC1CCC(=O)N1 HOBJEFOCIRXQKH-UHFFFAOYSA-N 0.000 description 1
- UAVFPPGKFIEEGW-UHFFFAOYSA-N 5-hydroxy-2-phenylbenzonitrile Chemical group N#CC1=CC(O)=CC=C1C1=CC=CC=C1 UAVFPPGKFIEEGW-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- LLIULJSIRLAGTK-UHFFFAOYSA-N CC1C(N(CC1)CCCC1=CC=CC=C1)=O Chemical compound CC1C(N(CC1)CCCC1=CC=CC=C1)=O LLIULJSIRLAGTK-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 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
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010014513 Embolism arterial Diseases 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- 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 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 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
- 244000131360 Morinda citrifolia Species 0.000 description 1
- LYXGPCCFLYQXMQ-UHFFFAOYSA-N NC(=N)c1ccc(cc1)-c1ccc(O)cc1 Chemical group NC(=N)c1ccc(cc1)-c1ccc(O)cc1 LYXGPCCFLYQXMQ-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 101800004937 Protein C Proteins 0.000 description 1
- 102000017975 Protein C Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- DXTBEGGSXUZVPZ-UHFFFAOYSA-N SS.SS Chemical compound SS.SS DXTBEGGSXUZVPZ-UHFFFAOYSA-N 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 101800001700 Saposin-D Proteins 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 208000032594 Vascular Remodeling Diseases 0.000 description 1
- 229920004482 WACKER® Polymers 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- JVQAIYIVIUCPBE-OLZOCXBDSA-N [(2s,4r)-4-(3-cyanopropyl)-1-(2-methylpropyl)-5-oxopyrrolidin-2-yl]methyl methanesulfonate Chemical compound CC(C)CN1[C@H](COS(C)(=O)=O)C[C@@H](CCCC#N)C1=O JVQAIYIVIUCPBE-OLZOCXBDSA-N 0.000 description 1
- YEINWPQEKLYUGY-ZJUUUORDSA-N [(2s,4r)-4-(3-cyanopropyl)-1-methyl-5-oxopyrrolidin-2-yl]methyl methanesulfonate Chemical compound CN1[C@H](COS(C)(=O)=O)C[C@@H](CCCC#N)C1=O YEINWPQEKLYUGY-ZJUUUORDSA-N 0.000 description 1
- AEHVYPVHMZKXMR-HLRBRJAUSA-N [2-(dimethylamino)-2-oxoethyl] 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.N1C(=O)[C@H](CC(=O)OCC(=O)N(C)C)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 AEHVYPVHMZKXMR-HLRBRJAUSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 208000037919 acquired disease Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 229940082988 antihypertensives serotonin antagonists Drugs 0.000 description 1
- 230000006502 antiplatelets effects Effects 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- KRWDGRGOFGAOHH-LJAQVGFWSA-N benzyl (5s)-2-oxo-5-(trityloxymethyl)pyrrolidine-1-carboxylate Chemical compound C([C@H]1COC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC(=O)N1C(=O)OCC1=CC=CC=C1 KRWDGRGOFGAOHH-LJAQVGFWSA-N 0.000 description 1
- ZHSWXWQJLHPXQA-UHFFFAOYSA-N benzyl (NE)-N-[amino-[4-(4-hydroxyphenyl)phenyl]methylidene]carbamate Chemical group C1=CC(O)=CC=C1C1=CC=C(C(=N)NC(=O)OCC=2C=CC=CC=2)C=C1 ZHSWXWQJLHPXQA-UHFFFAOYSA-N 0.000 description 1
- HRSQSGGNXFKKTK-UEMXOEKYSA-N benzyl 2-[(3S,5S)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate hydrochloride Chemical compound Cl.C1=CC(C(=N)N)=CC=C1C(C=C1)=CC=C1OC[C@H]1N(CCCC=2C=CC=CC=2)C(=O)[C@H](CC(=O)OCC=2C=CC=CC=2)C1 HRSQSGGNXFKKTK-UEMXOEKYSA-N 0.000 description 1
- BUDGTFYUBNOBEU-ZEQRLZLVSA-N benzyl 2-[(3s,5s)-5-[[4-[4-[(e)-n'-methoxycarbonylcarbamimidoyl]phenyl]phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound C1=CC(C(=N)NC(=O)OC)=CC=C1C(C=C1)=CC=C1OC[C@H]1NC(=O)[C@H](CC(=O)OCC=2C=CC=CC=2)C1 BUDGTFYUBNOBEU-ZEQRLZLVSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000008364 bulk solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- RJQLYIPXWDIJQV-PMACEKPBSA-N butyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound N1C(=O)[C@H](CC(=O)OCCCC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 RJQLYIPXWDIJQV-PMACEKPBSA-N 0.000 description 1
- SUKBZYFIOOKFHR-SFTDATJTSA-N butyl 2-[(3s,5s)-5-[[4-[4-[(z)-n'-methoxycarbonylcarbamimidoyl]phenyl]phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound N1C(=O)[C@H](CC(=O)OCCCC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(=N)NC(=O)OC)C=C1 SUKBZYFIOOKFHR-SFTDATJTSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 1
- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexyl-acetic acid Natural products OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 description 1
- 238000005661 deetherification reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- AQZWKPDVWWJWRY-UHFFFAOYSA-N ethyl 2-(2-oxopyrrolidin-1-yl)acetate Chemical compound CCOC(=O)CN1CCCC1=O AQZWKPDVWWJWRY-UHFFFAOYSA-N 0.000 description 1
- GYUAESUAOFBFQS-GOTSBHOMSA-N ethyl 2-[(3s,5s)-2-oxo-5-[[4-[4-[(e)-n'-phenoxycarbonylcarbamimidoyl]phenyl]phenoxy]methyl]pyrrolidin-3-yl]acetate Chemical compound N1C(=O)[C@H](CC(=O)OCC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(=N)NC(=O)OC=2C=CC=CC=2)C=C1 GYUAESUAOFBFQS-GOTSBHOMSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- PDKDIIUTUMMMNY-UHFFFAOYSA-N methyl 2-(2-oxo-1-phenylpyrrolidin-3-yl)acetate Chemical compound COC(=O)CC1C(N(CC1)C1=CC=CC=C1)=O PDKDIIUTUMMMNY-UHFFFAOYSA-N 0.000 description 1
- HPDZYDTXCOFUOY-UHFFFAOYSA-N methyl 2-(2-oxopyrrolidin-1-yl)acetate Chemical compound COC(=O)CN1CCCC1=O HPDZYDTXCOFUOY-UHFFFAOYSA-N 0.000 description 1
- YLZHBTAKVXDFGG-UHFFFAOYSA-N methyl 2-(2-oxopyrrolidin-3-yl)acetate Chemical compound COC(=O)CC1CCNC1=O YLZHBTAKVXDFGG-UHFFFAOYSA-N 0.000 description 1
- UQQGXCFGKBUPPZ-UHFFFAOYSA-N methyl 2-(2-oxopyrrolidin-3-yl)acetate hydrochloride Chemical compound Cl.COC(=O)CC1CCNC1=O UQQGXCFGKBUPPZ-UHFFFAOYSA-N 0.000 description 1
- KELLXPNFTSRNME-GBNZRNLASA-N methyl 2-[(3R,5R)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate hydrochloride Chemical compound Cl.C(N)(=N)C1=CC=C(C=C1)C1=CC=C(C=C1)OC[C@H]1C[C@@H](C(N1)=O)CC(=O)OC KELLXPNFTSRNME-GBNZRNLASA-N 0.000 description 1
- ADOHWSAAYUDSJS-UIOOFZCWSA-N methyl 2-[(3S,5S)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[3-(3,4-dimethoxyphenyl)propyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound C(N)(=N)C1=CC=C(C=C1)C1=CC=C(C=C1)OC[C@@H]1C[C@H](C(N1CCCC1=CC(=C(C=C1)OC)OC)=O)CC(=O)OC ADOHWSAAYUDSJS-UIOOFZCWSA-N 0.000 description 1
- UHOHGEZLIGNNFH-KAYWLYCHSA-N methyl 2-[(3r,5r)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@H]1C[C@@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 UHOHGEZLIGNNFH-KAYWLYCHSA-N 0.000 description 1
- LFHLXAJFCBJXOT-QGLFPKSOSA-N methyl 2-[(3r,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 LFHLXAJFCBJXOT-QGLFPKSOSA-N 0.000 description 1
- KELLXPNFTSRNME-PPPUBMIESA-N methyl 2-[(3r,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.N1C(=O)[C@@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 KELLXPNFTSRNME-PPPUBMIESA-N 0.000 description 1
- UULPFUBLMGSRAJ-UKOKCHKQSA-N methyl 2-[(3s,5s)-1-[2-(benzenesulfonyl)ethyl]-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CCS(=O)(=O)C=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 UULPFUBLMGSRAJ-UKOKCHKQSA-N 0.000 description 1
- NDJQNQQKZROKIY-DKIIUIKKSA-N methyl 2-[(3s,5s)-1-[2-(benzylamino)-2-oxoethyl]-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CC(=O)NCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 NDJQNQQKZROKIY-DKIIUIKKSA-N 0.000 description 1
- WPGJRYFNVATJJP-HEVIKAOCSA-N methyl 2-[(3s,5s)-1-[3-(3-benzylphenyl)propyl]-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=C(CC=2C=CC=CC=2)C=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 WPGJRYFNVATJJP-HEVIKAOCSA-N 0.000 description 1
- QJEOFGLWUHMRPG-JDXGNMNLSA-N methyl 2-[(3s,5s)-1-[3-(4-tert-butylphenyl)propyl]-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC(=CC=1)C(C)(C)C)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 QJEOFGLWUHMRPG-JDXGNMNLSA-N 0.000 description 1
- UVGZAITZTOKBAO-UKOKCHKQSA-N methyl 2-[(3s,5s)-1-benzyl-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 UVGZAITZTOKBAO-UKOKCHKQSA-N 0.000 description 1
- JSGWRFOIHDKCFH-DQEYMECFSA-N methyl 2-[(3s,5s)-1-benzyl-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 JSGWRFOIHDKCFH-DQEYMECFSA-N 0.000 description 1
- QTUXHMIFCAHHMB-ZEQRLZLVSA-N methyl 2-[(3s,5s)-2-oxo-5-[[4-[4-[(e)-n'-phenylmethoxycarbonylcarbamimidoyl]phenyl]phenoxy]methyl]pyrrolidin-3-yl]acetate Chemical compound N1C(=O)[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(=N)NC(=O)OCC=2C=CC=CC=2)C=C1 QTUXHMIFCAHHMB-ZEQRLZLVSA-N 0.000 description 1
- JWVSEPDCUMLONA-GJZGRUSLSA-N methyl 2-[(3s,5s)-5-(hydroxymethyl)-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound O=C1[C@H](CC(=O)OC)C[C@@H](CO)N1CCCC1=CC=CC=C1 JWVSEPDCUMLONA-GJZGRUSLSA-N 0.000 description 1
- FRATWIOYXCBAQO-JQWIXIFHSA-N methyl 2-[(3s,5s)-5-(hydroxymethyl)-2-oxo-1-phenylpyrrolidin-3-yl]acetate Chemical compound O=C1[C@H](CC(=O)OC)C[C@@H](CO)N1C1=CC=CC=C1 FRATWIOYXCBAQO-JQWIXIFHSA-N 0.000 description 1
- PTYPTIGEJANHOJ-WDSKDSINSA-N methyl 2-[(3s,5s)-5-(hydroxymethyl)-2-oxopyrrolidin-3-yl]acetate Chemical compound COC(=O)C[C@@H]1C[C@@H](CO)NC1=O PTYPTIGEJANHOJ-WDSKDSINSA-N 0.000 description 1
- MTJBZYQEBFDOHK-AAEUAGOBSA-N methyl 2-[(3s,5s)-5-(methylsulfonyloxymethyl)-2-oxo-1-phenylpyrrolidin-3-yl]acetate Chemical compound O=C1[C@H](CC(=O)OC)C[C@@H](COS(C)(=O)=O)N1C1=CC=CC=C1 MTJBZYQEBFDOHK-AAEUAGOBSA-N 0.000 description 1
- SSQCLMZWNFFOLU-NSOVKSMOSA-N methyl 2-[(3s,5s)-5-[[2-acetamido-4-(4-cyanophenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C(=C1)NC(C)=O)=CC=C1C1=CC=C(C#N)C=C1 SSQCLMZWNFFOLU-NSOVKSMOSA-N 0.000 description 1
- VLZLQZYJOCNFJP-FUZBZPTKSA-N methyl 2-[(3s,5s)-5-[[4-(3-carbamimidoylphenyl)sulfinylphenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1S(=O)C1=CC=CC(C(N)=N)=C1 VLZLQZYJOCNFJP-FUZBZPTKSA-N 0.000 description 1
- MLNKLMBXBLFFDI-DQEYMECFSA-N methyl 2-[(3s,5s)-5-[[4-(3-cyanophenyl)sulfanylphenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1SC1=CC=CC(C#N)=C1 MLNKLMBXBLFFDI-DQEYMECFSA-N 0.000 description 1
- ZLAAVEJDUDDBIJ-CCQIZPNASA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)-2-methylsulfanylphenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C(=C1)SC)=CC=C1C1=CC=C(C(N)=N)C=C1 ZLAAVEJDUDDBIJ-CCQIZPNASA-N 0.000 description 1
- SOHREOMELXEHPH-MJUPOSSGSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)-2-methylsulfinylphenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C(=C1)S(C)=O)=CC=C1C1=CC=C(C(N)=N)C=C1 SOHREOMELXEHPH-MJUPOSSGSA-N 0.000 description 1
- AJSPREPIXNELGK-HLRBRJAUSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.OCCN1C(=O)[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 AJSPREPIXNELGK-HLRBRJAUSA-N 0.000 description 1
- YIYUASNNVXFZSZ-VROPFNGYSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-(2-morpholin-4-yl-2-oxoethyl)-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CC(=O)N1CCOCC1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 YIYUASNNVXFZSZ-VROPFNGYSA-N 0.000 description 1
- UULHBKRPXQPYRW-IUQUCOCYSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-(3-carbamoylphenyl)-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1C=1C=C(C=CC=1)C(N)=O)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 UULHBKRPXQPYRW-IUQUCOCYSA-N 0.000 description 1
- WEUYJXRHRFHPTO-BCGXTZKJSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-(3-methylsulfinylpropyl)-2-oxopyrrolidin-3-yl]acetate Chemical compound CS(=O)CCCN1C(=O)[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 WEUYJXRHRFHPTO-BCGXTZKJSA-N 0.000 description 1
- MFFKGCFNVCLUJM-UEMXOEKYSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-(4,4-diphenylbutyl)-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CCCC(C=1C=CC=CC=1)C=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 MFFKGCFNVCLUJM-UEMXOEKYSA-N 0.000 description 1
- OVABIVLZNHAULP-CWAVIJBDSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[3-(2,4-dichlorophenyl)propyl]-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CCCC=1C(=CC(Cl)=CC=1)Cl)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 OVABIVLZNHAULP-CWAVIJBDSA-N 0.000 description 1
- HGPYQBAAZRBLEK-CCQIZPNASA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-[3-(4-methylsulfanylphenyl)propyl]-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CCCC=1C=CC(SC)=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 HGPYQBAAZRBLEK-CCQIZPNASA-N 0.000 description 1
- PJHOYHWEZHDTOH-APTPAJQOSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-1-methyl-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.CN1C(=O)[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 PJHOYHWEZHDTOH-APTPAJQOSA-N 0.000 description 1
- KCDRMFHFDSRAJR-VROPFNGYSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxo-1-(2-oxo-2-piperazin-1-ylethyl)pyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CC(=O)N1CCNCC1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 KCDRMFHFDSRAJR-VROPFNGYSA-N 0.000 description 1
- KTVILXLJEKQHIN-UKOKCHKQSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxo-1-(2-phenylsulfanylethyl)pyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CCSC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 KTVILXLJEKQHIN-UKOKCHKQSA-N 0.000 description 1
- LFHLXAJFCBJXOT-CCQIZPNASA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 LFHLXAJFCBJXOT-CCQIZPNASA-N 0.000 description 1
- HVYDJMADPLARCL-YLQNXEDKSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxo-1-[3-[3-(trifluoromethyl)phenyl]propyl]pyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CCCC=1C=C(C=CC=1)C(F)(F)F)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 HVYDJMADPLARCL-YLQNXEDKSA-N 0.000 description 1
- JLZNGMXUMZPWDZ-CPTHQKRGSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxo-1-phenylpyrrolidin-3-yl]acetate;hydrate;hydrochloride Chemical compound O.Cl.C([C@@H]1C[C@H](C(N1C=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=N)C=C1 JLZNGMXUMZPWDZ-CPTHQKRGSA-N 0.000 description 1
- KELLXPNFTSRNME-QJHJCNPRSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamimidoylphenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.N1C(=O)[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(N)=N)C=C1 KELLXPNFTSRNME-QJHJCNPRSA-N 0.000 description 1
- IZHPUHPRLBQHQC-ZEQRLZLVSA-N methyl 2-[(3s,5s)-5-[[4-(4-carbamoyl-3-chlorophenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C(N)=O)C(Cl)=C1 IZHPUHPRLBQHQC-ZEQRLZLVSA-N 0.000 description 1
- ZEVAZJHCJYMRES-SVBPBHIXSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyano-2-methylphenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1C ZEVAZJHCJYMRES-SVBPBHIXSA-N 0.000 description 1
- FLIXFYSFVFZZTF-NSOVKSMOSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)-2,3-dimethylphenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C(=C1C)C)=CC=C1C1=CC=C(C#N)C=C1 FLIXFYSFVFZZTF-NSOVKSMOSA-N 0.000 description 1
- MVINIKHHIOXHKT-SVBPBHIXSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)-2-(methanesulfonamido)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C(=C1)NS(C)(=O)=O)=CC=C1C1=CC=C(C#N)C=C1 MVINIKHHIOXHKT-SVBPBHIXSA-N 0.000 description 1
- BVSDIFWFRWZPJX-UIOOFZCWSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)-2-fluorophenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C(=C1)F)=CC=C1C1=CC=C(C#N)C=C1 BVSDIFWFRWZPJX-UIOOFZCWSA-N 0.000 description 1
- KLXPEGJHFLUIEA-SVBPBHIXSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)-2-methylsulfanylphenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C(=C1)SC)=CC=C1C1=CC=C(C#N)C=C1 KLXPEGJHFLUIEA-SVBPBHIXSA-N 0.000 description 1
- AHNQUIWFDDOLKO-UIOOFZCWSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)-2-nitrophenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C(=C1)[N+]([O-])=O)=CC=C1C1=CC=C(C#N)C=C1 AHNQUIWFDDOLKO-UIOOFZCWSA-N 0.000 description 1
- YHSFJCBAEUHMFM-SVBPBHIXSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-1-(3-cyclohexylpropyl)-2-oxopyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC1CCCCC1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 YHSFJCBAEUHMFM-SVBPBHIXSA-N 0.000 description 1
- KFFDOIMEANBWPB-LQJZCPKCSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-1-(4,4-diphenylbutyl)-2-oxopyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC(C=1C=CC=CC=1)C=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 KFFDOIMEANBWPB-LQJZCPKCSA-N 0.000 description 1
- QVSYBKYUVXEHDI-AHWVRZQESA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-1-[3-(2,4-dichlorophenyl)propyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C(=CC(Cl)=CC=1)Cl)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 QVSYBKYUVXEHDI-AHWVRZQESA-N 0.000 description 1
- VNZKXEOZOHJYCV-PXNSSMCTSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-1-methylpyrrolidin-3-yl]acetate Chemical compound CN1C[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C#N)C=C1 VNZKXEOZOHJYCV-PXNSSMCTSA-N 0.000 description 1
- UHOHGEZLIGNNFH-SVBPBHIXSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 UHOHGEZLIGNNFH-SVBPBHIXSA-N 0.000 description 1
- DFZNXHISOCQJRS-SVBPBHIXSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxo-1-(4-phenoxybutyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCCOC=1C=CC=CC=1)=O)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 DFZNXHISOCQJRS-SVBPBHIXSA-N 0.000 description 1
- SSJOZJXYWFYWMW-DHIFEGFHSA-N methyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-3-methyl-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@@](C(N1CCCC=1C=CC=CC=1)=O)(C)CC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 SSJOZJXYWFYWMW-DHIFEGFHSA-N 0.000 description 1
- RKSAIGIZWRKVIJ-HOTGVXAUSA-N methyl 2-[(3s,5s)-5-[[4-[3-chloro-4-[(e)-n'-methoxycarbonylcarbamimidoyl]phenyl]phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound N1C(=O)[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=C(Cl)C(C(=N)NC(=O)OC)=CC=2)C=C1 RKSAIGIZWRKVIJ-HOTGVXAUSA-N 0.000 description 1
- RYMOZWFRQBPPRI-HLRBRJAUSA-N methyl 2-[(3s,5s)-5-[[4-[4-(2-aminoethyl)phenyl]phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate;hydrochloride Chemical compound Cl.N1C(=O)[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(CCN)=CC=2)C=C1 RYMOZWFRQBPPRI-HLRBRJAUSA-N 0.000 description 1
- PVFBTQOVUGWWOF-GOTSBHOMSA-N methyl 2-[(3s,5s)-5-[[4-[4-(n'-benzoylcarbamimidoyl)phenyl]phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound N1C(=O)[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C(=N)NC(=O)C=2C=CC=CC=2)C=C1 PVFBTQOVUGWWOF-GOTSBHOMSA-N 0.000 description 1
- YCRVZQHXXDEHST-OALUTQOASA-N methyl 2-[(3s,5s)-5-[[4-[4-[(e)-n'-ethoxycarbonylcarbamimidoyl]phenyl]phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound C1=CC(C(=N)NC(=O)OCC)=CC=C1C(C=C1)=CC=C1OC[C@H]1NC(=O)[C@H](CC(=O)OC)C1 YCRVZQHXXDEHST-OALUTQOASA-N 0.000 description 1
- WJNVHRKMSZSZKG-OALUTQOASA-N methyl 2-[(3s,5s)-5-[[4-[4-[(methoxycarbonylamino)methyl]phenyl]phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound N1C(=O)[C@H](CC(=O)OC)C[C@H]1COC1=CC=C(C=2C=CC(CNC(=O)OC)=CC=2)C=C1 WJNVHRKMSZSZKG-OALUTQOASA-N 0.000 description 1
- CUDMQHCSBUYCCJ-BDYUSTAISA-N methyl 2-[(3s,5s)-5-[[[3-(3-aminophenyl)benzoyl]amino]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)OC)NC(=O)C(C=1)=CC=CC=1C1=CC=CC(N)=C1 CUDMQHCSBUYCCJ-BDYUSTAISA-N 0.000 description 1
- IKPHMCNRVDRDCR-WDYNHAJCSA-N methyl 4-[(3r,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]butanoate Chemical compound C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CCCC(=O)OC)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 IKPHMCNRVDRDCR-WDYNHAJCSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- NJHQZERADYZTNP-MLGYITDRSA-N n-butyl-2-[(3s,5s)-5-[[4-[4-(n'-butylcarbamimidoyl)phenyl]phenoxy]methyl]-2-oxo-1-(3-phenylpropyl)pyrrolidin-3-yl]acetamide;hydrochloride Chemical compound Cl.C([C@@H]1C[C@H](C(N1CCCC=1C=CC=CC=1)=O)CC(=O)NCCCC)OC(C=C1)=CC=C1C1=CC=C(C(=N)NCCCC)C=C1 NJHQZERADYZTNP-MLGYITDRSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 235000017524 noni Nutrition 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 229940109615 oxy 10 Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-M periodate Chemical compound [O-]I(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-M 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- BYTCDABWEGFPLT-UHFFFAOYSA-L potassium;sodium;dihydroxide Chemical compound [OH-].[OH-].[Na+].[K+] BYTCDABWEGFPLT-UHFFFAOYSA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 229960000856 protein c Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 108010073863 saruplase Proteins 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- LDTLADDKFLAYJA-UHFFFAOYSA-L sodium metabisulphite Chemical compound [Na+].[Na+].[O-]S(=O)OS([O-])=O LDTLADDKFLAYJA-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- NWJXGWYJXNTBKO-YUMQZZPRSA-N tert-butyl 2-[(3s,5s)-5-(hydroxymethyl)-2-oxopyrrolidin-3-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@@H]1C[C@@H](CO)NC1=O NWJXGWYJXNTBKO-YUMQZZPRSA-N 0.000 description 1
- XOZVRFKSOHQNSB-DQEYMECFSA-N tert-butyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-1-(2-morpholin-4-yl-2-oxoethyl)-2-oxopyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CC(=O)N1CCOCC1)=O)CC(=O)OC(C)(C)C)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 XOZVRFKSOHQNSB-DQEYMECFSA-N 0.000 description 1
- DRVAYFMDMNLNRT-DQEYMECFSA-N tert-butyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxo-1-(2-oxo-2-pyrrolidin-1-ylethyl)pyrrolidin-3-yl]acetate Chemical compound C([C@@H]1C[C@H](C(N1CC(=O)N1CCCC1)=O)CC(=O)OC(C)(C)C)OC(C=C1)=CC=C1C1=CC=C(C#N)C=C1 DRVAYFMDMNLNRT-DQEYMECFSA-N 0.000 description 1
- IEQKJZVPAYSAMA-PMACEKPBSA-N tert-butyl 2-[(3s,5s)-5-[[4-(4-cyanophenyl)phenoxy]methyl]-2-oxopyrrolidin-3-yl]acetate Chemical compound N1C(=O)[C@H](CC(=O)OC(C)(C)C)C[C@H]1COC1=CC=C(C=2C=CC(=CC=2)C#N)C=C1 IEQKJZVPAYSAMA-PMACEKPBSA-N 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
- 229940019333 vitamin k antagonists Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyrrole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Detergent Compositions (AREA)
- Indole Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4035961 | 1990-11-02 | ||
DE4035961A DE4035961A1 (de) | 1990-11-02 | 1990-11-02 | Cyclische iminoderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
Publications (3)
Publication Number | Publication Date |
---|---|
FI915136A0 FI915136A0 (fi) | 1991-10-31 |
FI915136A FI915136A (fi) | 1992-05-03 |
FI107606B true FI107606B (fi) | 2001-09-14 |
Family
ID=6418111
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FI915136A FI107606B (fi) | 1990-11-02 | 1991-10-31 | Menetelmä valmistaa farmaseuttisesti arvokkaita 1-, 3-, 5-substituoituja pyrrolidin-2-oneja |
Country Status (25)
Country | Link |
---|---|
US (2) | US5541343A (ko) |
EP (1) | EP0483667B1 (ko) |
JP (1) | JP2937589B2 (ko) |
KR (1) | KR100223135B1 (ko) |
AT (1) | ATE163008T1 (ko) |
BG (1) | BG62025B2 (ko) |
BR (1) | BR1100445A (ko) |
CA (1) | CA2054850C (ko) |
DE (2) | DE4035961A1 (ko) |
DK (1) | DK0483667T3 (ko) |
EE (1) | EE03099B1 (ko) |
ES (1) | ES2113867T3 (ko) |
FI (1) | FI107606B (ko) |
GR (1) | GR3026508T3 (ko) |
HK (1) | HK1008742A1 (ko) |
HU (2) | HUT67288A (ko) |
IE (1) | IE913822A1 (ko) |
IL (1) | IL99926A (ko) |
MX (1) | MX9203677A (ko) |
NO (1) | NO174806B (ko) |
NZ (1) | NZ240463A (ko) |
PT (1) | PT99402B (ko) |
RU (1) | RU2040519C1 (ko) |
SG (1) | SG81852A1 (ko) |
ZA (1) | ZA918734B (ko) |
Families Citing this family (89)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4127404A1 (de) * | 1991-08-19 | 1993-02-25 | Thomae Gmbh Dr K | Cyclische iminoderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
US5294713A (en) * | 1991-08-23 | 1994-03-15 | Takeda Chemical Industries, Ltd. | 2-piperazinone compounds and their use |
ES2092170T3 (es) * | 1992-04-28 | 1996-11-16 | Thomae Gmbh Dr K | Antagonistas de receptores de fibrinogeno marcados con tritio, su utilizacion y procedimiento para su preparacion. |
DE4213931A1 (de) * | 1992-04-28 | 1993-11-04 | Thomae Gmbh Dr K | Cyclische iminoderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
DE4213919A1 (de) * | 1992-04-28 | 1993-11-04 | Thomae Gmbh Dr K | Cyclische iminoderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
DE4219158A1 (de) * | 1992-06-11 | 1993-12-16 | Thomae Gmbh Dr K | Biphenylderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
DE4241632A1 (de) * | 1992-12-10 | 1994-06-16 | Thomae Gmbh Dr K | Carbonsäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
US5314902A (en) * | 1993-01-27 | 1994-05-24 | Monsanto Company | Urea derivatives useful as platelet aggregation inhibitors |
JP3034046B2 (ja) * | 1993-03-31 | 2000-04-17 | ジー.ディー.サール アンド カンパニー | 血小板凝集阻害剤としての1−アミジノフェニル−ピロリドンピペリジノンアゼチノン |
US6169107B1 (en) | 1993-04-28 | 2001-01-02 | Sumitomo Pharmaceutical Co., Ltd. | Indoloylguanidine derivatives |
DE4424975A1 (de) * | 1994-07-15 | 1996-01-18 | Thomae Gmbh Dr K | 2-Piperidinone, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
JPH10511374A (ja) * | 1994-12-23 | 1998-11-04 | ドクトル カルル トーマエ ゲゼルシャフト ミット ベシュレンクテル ハフツング | ピペラジン誘導体、これらの化合物を含む医薬品、それらの使用及びそれらの調製方法 |
ATE215074T1 (de) * | 1995-04-26 | 2002-04-15 | Takeda Chemical Industries Ltd | Piperazinone als inhibitoren von blutplattchenaggregation |
DE19515500A1 (de) * | 1995-04-27 | 1996-10-31 | Thomae Gmbh Dr K | Substituierte Phenylamidine, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
US5719296A (en) * | 1995-10-30 | 1998-02-17 | Merck & Co., Inc. | Pseudopeptide lactam inhibitors of peptide binding to MHC class II proteins |
DE19604191A1 (de) * | 1996-02-06 | 1997-08-07 | Hoechst Schering Agrevo Gmbh | 2,4-Diamino-1,3,5-triazine, Verfahren zu deren Herstellung und deren Verwendung als Herbizide und Pflanzenwachstumsregulatoren |
US5942544A (en) * | 1996-02-22 | 1999-08-24 | Dupont Pharmaceuticals Company | α-branched anilines, toluenes, and analogs thereof as factor Xa inhibitors |
DE19621482A1 (de) | 1996-05-29 | 1997-12-04 | Hoechst Ag | Substituierte 1-Naphthoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
DE19621483A1 (de) * | 1996-05-29 | 1997-12-04 | Hoechst Ag | Substituierte 2-Naphthoylguanidine, Verfahren zur ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
US6057342A (en) * | 1996-08-16 | 2000-05-02 | Dupont Pharmaceutical Co. | Amidinophenyl-pyrrolidines, -pyrrolines, and -isoxazolidines and derivatives thereof |
CA2262117A1 (en) * | 1996-08-16 | 1998-02-19 | The Dupont Merck Pharmaceutical Company | Amidinophenyl-pyrrolidines, -pyrrolines, and -isoxazolidines and derivatives thereof |
AU8875798A (en) * | 1997-08-29 | 1999-03-22 | Proteus Molecular Design Ltd | Meta-benzamidine derivatives as serin protease inhibitors |
US6740682B2 (en) | 1997-08-29 | 2004-05-25 | Tularik Limited | Meta-benzamidine derivatives as serine protease inhibitors |
EP1015427A1 (en) | 1997-09-08 | 2000-07-05 | Georgetown University | Substituted 2-pyrrolidinone activators of pkc |
WO1999026919A1 (fr) * | 1997-11-20 | 1999-06-03 | Teijin Limited | Derives de biphenylamidine |
CA2333927A1 (en) | 1998-04-01 | 1999-10-07 | Dupont Pharmaceuticals Company | Pyrimidines and triazines as integrin antagonists |
AU3406599A (en) * | 1998-04-09 | 1999-11-01 | Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin | Novel benzyl guanidine derivatives for therapy and (in-vivo) and (in-vitro) diagnosis |
SG74717A1 (en) | 1998-04-10 | 2000-08-22 | Japan Tobacco Inc | Amidine compound |
US6518305B1 (en) | 1998-04-23 | 2003-02-11 | Abbott Laboratories | Five-membered carbocyclic and heterocyclic inhibitors of neuraminidases |
US6455571B1 (en) | 1998-04-23 | 2002-09-24 | Abbott Laboratories | Inhibitors of neuraminidases |
HUP0101224A3 (en) * | 1998-04-23 | 2002-12-28 | Abbott Lab | Pyrrolidine derivatives as inhibitors of neuraminidases and pharmaceutical compositions containing them |
ATE266662T1 (de) | 1998-07-22 | 2004-05-15 | Daiichi Suntory Pharma Co Ltd | Nf-kappa b inhibitoren, die indanderivate als aktiven bestandteil enthalten |
US6284796B1 (en) * | 1998-08-06 | 2001-09-04 | Abbott Laboratories | Ukokinase inhibitors |
DE19844787A1 (de) * | 1998-09-30 | 2000-04-13 | Boehringer Ingelheim Pharma | Disubstituierte Pyrrolidinone, diese Verbindung enthaltende Arzneimittel und deren Verwendung sowie ihre Herstellung |
US6372764B1 (en) | 1999-03-02 | 2002-04-16 | Merck & Co., Inc. | Pyrrolidine modulators of chemokine receptor activity |
US6362201B1 (en) | 1999-03-02 | 2002-03-26 | Merck & Co., Inc. | 3-cyclopropyl and 3-cyclobutyl pyrrolidine modulators of chemokine receptor activity |
WO2000051998A1 (en) | 1999-03-02 | 2000-09-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cathepsin s |
WO2000051609A1 (en) * | 1999-03-02 | 2000-09-08 | Merck & Co., Inc. | 3-alkyl substituted pyrrolidine modulators of chemokine receptor activity |
US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
FR2817257B1 (fr) * | 2000-11-30 | 2009-03-20 | Sanofi Synthelabo | Cyclohexyl(alkyl)-propanolamines, leur preparation et compositions pharmaceutiques en contenant |
CA2436774A1 (en) * | 2001-01-30 | 2002-08-08 | R. Michael Lawrence | Sulfonamide lactam inhibitors of factor xa |
DE10121003A1 (de) * | 2001-04-28 | 2002-12-19 | Aventis Pharma Gmbh | Anthranilsäureamide, Verfahren zur Herstellung, ihrer Verwendung als Medikament sowie sie enthaltende pharmazeutische Zubereitungen |
GB0114004D0 (en) | 2001-06-08 | 2001-08-01 | Glaxo Group Ltd | Chemical compounds |
GB0114005D0 (en) | 2001-06-08 | 2001-08-01 | Glaxo Group Ltd | Chemical compounds |
ATE367812T1 (de) * | 2001-06-20 | 2007-08-15 | Wyeth Corp | Substituierte indolsäurederivate als inhibitoren von plasminogen-aktivator-inhibitor-1 (pai-1) |
TWI224101B (en) * | 2001-06-20 | 2004-11-21 | Wyeth Corp | Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1) |
CA2509238A1 (en) * | 2002-12-10 | 2004-06-24 | Wyeth | Substituted 3-carbonyl-1h-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) |
US7348351B2 (en) * | 2002-12-10 | 2008-03-25 | Wyeth | Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
CA2509191A1 (en) * | 2002-12-10 | 2004-06-24 | Wyeth | Aryl, aryloxy, and alkyloxy substituted 1h-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) |
UA80453C2 (en) * | 2002-12-10 | 2007-09-25 | Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1) | |
JP2006516593A (ja) * | 2003-02-07 | 2006-07-06 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Mmp−9依存性疾患の治療及び予防のためのジピリダモール又はモピダモールの使用 |
WO2004093881A2 (en) | 2003-04-24 | 2004-11-04 | Boehringer Ingelheim International Gmbh | Use of dipyridamole or mopidamole for treatment and prevention of thrombo-embolic diseases and disorders caused by excessive formation of thrombin and/or by elevated expression of thrombin receptors |
AU2004238607B2 (en) * | 2003-05-16 | 2010-05-27 | Merck Sharp & Dohme Limited | Cyclohexyl sulphones as gamma-secretase inhibitors |
US7163954B2 (en) * | 2003-09-25 | 2007-01-16 | Wyeth | Substituted naphthyl benzothiophene acids |
US7411083B2 (en) | 2003-09-25 | 2008-08-12 | Wyeth | Substituted acetic acid derivatives |
US7141592B2 (en) * | 2003-09-25 | 2006-11-28 | Wyeth | Substituted oxadiazolidinediones |
US7268159B2 (en) * | 2003-09-25 | 2007-09-11 | Wyeth | Substituted indoles |
US7351726B2 (en) * | 2003-09-25 | 2008-04-01 | Wyeth | Substituted oxadiazolidinediones |
US7265148B2 (en) * | 2003-09-25 | 2007-09-04 | Wyeth | Substituted pyrrole-indoles |
US7420083B2 (en) * | 2003-09-25 | 2008-09-02 | Wyeth | Substituted aryloximes |
US7442805B2 (en) * | 2003-09-25 | 2008-10-28 | Wyeth | Substituted sulfonamide-indoles |
US7332521B2 (en) * | 2003-09-25 | 2008-02-19 | Wyeth | Substituted indoles |
US7534894B2 (en) | 2003-09-25 | 2009-05-19 | Wyeth | Biphenyloxy-acids |
US7446201B2 (en) * | 2003-09-25 | 2008-11-04 | Wyeth | Substituted heteroaryl benzofuran acids |
US7342039B2 (en) * | 2003-09-25 | 2008-03-11 | Wyeth | Substituted indole oximes |
US7582773B2 (en) * | 2003-09-25 | 2009-09-01 | Wyeth | Substituted phenyl indoles |
US7759387B2 (en) | 2003-10-08 | 2010-07-20 | Piramal Life Sciences Limited | Fibrinogen receptor antagonists and their use |
BRPI0507374A (pt) * | 2004-02-02 | 2007-07-10 | Pfizer Prod Inc | moduladores do receptor de histamina-3 |
JP5014983B2 (ja) | 2004-05-07 | 2012-08-29 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 11−ベータヒドロキシステロイドデヒドロゲナーゼ阻害剤としてのピロリジン−2−オン及びピペリジン−2−オン誘導体 |
CN101044136A (zh) * | 2004-08-23 | 2007-09-26 | 惠氏公司 | 作为pai-1抑制剂的吡咯基-萘基酸 |
US7754747B2 (en) * | 2004-08-23 | 2010-07-13 | Wyeth Llc | Oxazolo-naphthyl acids |
AU2005277139A1 (en) * | 2004-08-23 | 2006-03-02 | Wyeth | Thiazolo-naphthyl acids as inhibitors of plasminogen activator inhibitor-1 |
JP5208505B2 (ja) * | 2004-08-30 | 2013-06-12 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 11−ベータヒドロキシステロイドデヒドロゲナーゼ阻害剤としてのn−2アダマンタニル−2−フェノキシ−アセトアミド誘導体 |
JP5137574B2 (ja) * | 2004-08-30 | 2013-02-06 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 11−ベータヒドロキシステロイドヒドロゲナーゼ阻害剤としての三環式ラクタム誘導体 |
DE602005017159D1 (de) | 2004-08-30 | 2009-11-26 | Janssen Pharmaceutica Nv | Oxysteroid-dehydrogenase-inhibitoren |
WO2006114096A1 (en) * | 2005-04-25 | 2006-11-02 | Danmarks Tekniske Universitet | Pyrrolidinone dipeptide analogs and use thereof as artificial sweeteners |
WO2007022321A2 (en) * | 2005-08-17 | 2007-02-22 | Wyeth | Substituted indoles and use thereof |
MX337100B (es) | 2007-10-05 | 2016-02-11 | Acucela Inc | Compuestos alcoxi para el tratamiento de enfermedades. |
CN101868455B (zh) * | 2007-10-23 | 2013-11-13 | 阿勒根公司 | 治疗性的取代的内酰胺 |
WO2011003103A2 (en) | 2009-07-02 | 2011-01-06 | Acucela, Inc. | Pharmacology of visual cycle modulators |
US20130267699A1 (en) | 2011-06-24 | 2013-10-10 | California Institute Of Technology | Quaternary heteroatom containing compounds |
US8822679B2 (en) * | 2011-06-24 | 2014-09-02 | California Institute Of Technology | Quaternary heteroatom containing compounds |
US9518034B2 (en) | 2013-10-14 | 2016-12-13 | California Institute Of Technology | Synthesis of chiral enaminones, their derivatives, and bioactivity studies thereof |
JP6431538B2 (ja) | 2013-11-21 | 2018-11-28 | マーケット ユニバーシティー | エストロゲン受容体ベータアイソフォームの選択的アゴニストとしての置換(4’−ヒドロキシフェニル)シクロアルカン化合物およびその使用 |
US10421696B2 (en) | 2014-12-18 | 2019-09-24 | California Institute Of Technology | Enantioselective synthesis of α-quaternary mannich adducts by palladium-catalyzed allylic alkylation |
CN107922373A (zh) | 2015-03-27 | 2018-04-17 | 加利福尼亚技术学院 | 使用低催化剂浓度和稳定的预催化剂的不对称催化脱羧烷基烷基化 |
US10040784B2 (en) | 2016-03-11 | 2018-08-07 | California Institute Of Technology | Compositions and methods for acylating lactams |
EP3480190B1 (en) | 2017-11-01 | 2023-01-04 | California Institute of Technology | Methods for enantioselective allylic alkylation of esters, lactones, and lactams with unactivated allylic alcohols |
US11214568B2 (en) | 2018-10-18 | 2022-01-04 | California Institute Of Technology | Gem-disubstituted pyrrolidines, piperazines, and diazepanes, and compositions and methods of making the same |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4247466A (en) * | 1979-07-05 | 1981-01-27 | American Cyanamid Company | Lactone metabolites of 3-(4-biphenylylcarbonyl)propionic acid |
EP0194548A3 (de) * | 1985-03-12 | 1988-08-17 | Dr. Karl Thomae GmbH | Neue Sulfonylaminoäthylverbindungen, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
FI89709C (fi) * | 1985-03-16 | 1993-11-10 | Wellcome Found | Foerfarande foer framstaellning av terapeutiskt anvaendbara arylderivat |
DE3823299A1 (de) * | 1988-07-07 | 1990-01-11 | Schering Ag | Substituierte phenyl-pyrrolidin-2-one, -oxazolidin-2-one und -imidazolidin-2-one, ihre herstellung sowie verwendung in arzneimitteln |
-
1990
- 1990-11-02 DE DE4035961A patent/DE4035961A1/de not_active Ceased
-
1991
- 1991-10-24 DK DK91118148T patent/DK0483667T3/da active
- 1991-10-24 DE DE59108930T patent/DE59108930D1/de not_active Expired - Lifetime
- 1991-10-24 ES ES91118148T patent/ES2113867T3/es not_active Expired - Lifetime
- 1991-10-24 AT AT91118148T patent/ATE163008T1/de not_active IP Right Cessation
- 1991-10-24 SG SG9601241A patent/SG81852A1/en unknown
- 1991-10-24 EP EP91118148A patent/EP0483667B1/de not_active Expired - Lifetime
- 1991-10-31 PT PT99402A patent/PT99402B/pt not_active IP Right Cessation
- 1991-10-31 FI FI915136A patent/FI107606B/fi not_active IP Right Cessation
- 1991-11-01 IE IE382291A patent/IE913822A1/en not_active IP Right Cessation
- 1991-11-01 NO NO914294A patent/NO174806B/no not_active IP Right Cessation
- 1991-11-01 IL IL9992691A patent/IL99926A/en not_active IP Right Cessation
- 1991-11-01 HU HU913455A patent/HUT67288A/hu unknown
- 1991-11-01 CA CA002054850A patent/CA2054850C/en not_active Expired - Lifetime
- 1991-11-01 RU SU915001905A patent/RU2040519C1/ru active
- 1991-11-01 JP JP3313154A patent/JP2937589B2/ja not_active Expired - Lifetime
- 1991-11-02 KR KR1019910019458A patent/KR100223135B1/ko not_active IP Right Cessation
- 1991-11-04 ZA ZA918734A patent/ZA918734B/xx unknown
- 1991-11-04 NZ NZ240463A patent/NZ240463A/en not_active IP Right Cessation
-
1992
- 1992-06-29 MX MX9203677A patent/MX9203677A/es unknown
-
1994
- 1994-01-25 BG BG98416A patent/BG62025B2/bg unknown
- 1994-11-23 EE EE9400438A patent/EE03099B1/xx not_active IP Right Cessation
- 1994-12-28 US US08/365,336 patent/US5541343A/en not_active Expired - Lifetime
-
1995
- 1995-06-01 US US08/458,096 patent/US5591769A/en not_active Expired - Lifetime
- 1995-06-02 HU HU95P/P00156P patent/HU211563A9/hu unknown
-
1997
- 1997-05-06 BR BR1100445-2A patent/BR1100445A/pt active IP Right Grant
-
1998
- 1998-04-03 GR GR980400691T patent/GR3026508T3/el unknown
- 1998-07-17 HK HK98109250A patent/HK1008742A1/xx not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
FI107606B (fi) | Menetelmä valmistaa farmaseuttisesti arvokkaita 1-, 3-, 5-substituoituja pyrrolidin-2-oneja | |
US5274104A (en) | N-substituted heterocyclic derivatives useful in the treatment of cardiovascular disorders | |
AU654372B2 (en) | Cyclic imino derivatives | |
AU654340B2 (en) | Urea derivatives | |
AU2002257970B2 (en) | Tricyclic compounds useful as angiotensin II agonists | |
US5576444A (en) | Cyclic imino derivatives, processes for preparing them and pharmaceutical compositions containing these compounds | |
SK94393A3 (en) | Cyclic derivatives of urea, process for their production and their pharmaceutical agents with the content of those | |
JP7446316B2 (ja) | 置換ピロリジンアミドiii | |
HUT59129A (en) | Method for producing azocyclic compounds | |
WO1996005194A1 (de) | Benzazepin cyclische harnstoffderivate mit aggregationshemmender wirkung | |
WO2010117796A2 (en) | Processes for the preparation of alpha-chloroketones from carboxylic acids | |
EP0268229B1 (en) | Imidazolidinone compounds, processes for preparation thereof, compositions comprising such compounds, and the use of such compounds for the manufacture of medicaments having therapeutic value | |
KR100400161B1 (ko) | Pdeiv및사이토킨억제활성을가진1,3-디하이드로-1-(페닐알케닐)-2h-이미다졸-2-온유도체 | |
NZ250002A (en) | Trisubstituted pyridone biphenyls and medicaments | |
JPH0625159A (ja) | 環状イミノ誘導体、これらの化合物を含む医薬組成物及びそれらの調製法 | |
Nicolai et al. | Synthesis and angiotensin II receptor antagonist activity of C-linked pyrazole derivatives | |
HU221190B1 (en) | Acyl-coenzyme-a-cholesterol-acyl-transferase (acat) inhibitor tetrazole-carboxamide derivatives | |
US4882343A (en) | Biarylalkylimidazole derivatives as anti-depressants | |
JPS59118784A (ja) | 置換イミダゾ〔1,5−a〕ピリジン及びその製造方法,並びに該化合物を含有する医薬 | |
BE1009376A4 (fr) | Derives du carboxymethylidenecycloheptimidazole, procede de preparation de ces derniers et agents therapeutiques contenant ces composes. | |
AU2004289685A1 (en) | Process for the synthesis of imidazoles | |
US6417203B1 (en) | Antithrombotic agents | |
US6114534A (en) | Carbamoly substituted heterocycles | |
MXPA99007603A (en) | Antitromboti agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MA | Patent expired |