FI107606B - Menetelmä valmistaa farmaseuttisesti arvokkaita 1-, 3-, 5-substituoituja pyrrolidin-2-oneja - Google Patents

Info

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

1990-11-02

Links

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• 238000002360 preparation method Methods 0.000 title claims abstract description 19
• 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 333
• 150000001875 compounds Chemical class 0.000 claims abstract description 78
• 150000003839 salts Chemical class 0.000 claims abstract description 22
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 135
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 59
• 125000004432 carbon atom Chemical group C* 0.000 claims description 43
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
• 239000000460 chlorine Substances 0.000 claims description 31
• 125000000217 alkyl group Chemical group 0.000 claims description 28
• 239000002253 acid Substances 0.000 claims description 25
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 19
• 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
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
• 229910052757 nitrogen Inorganic materials 0.000 claims description 12
• 239000011541 reaction mixture Substances 0.000 claims description 12
• 125000003545 alkoxy group Chemical group 0.000 claims description 11
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 11
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
• 239000001257 hydrogen Substances 0.000 claims description 10
• 229910052739 hydrogen Inorganic materials 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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 8
• 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
• 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
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 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
• 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
• 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 4
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 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
• 125000002947 alkylene group Chemical group 0.000 claims description 3
• 150000001408 amides Chemical class 0.000 claims description 3
• 125000004103 aminoalkyl group Chemical group 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
• 125000004433 nitrogen atom Chemical group N* 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
• 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
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
• 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 2
• 125000002071 phenylalkoxy group Chemical group 0.000 claims description 2
• 125000004646 sulfenyl group Chemical group S(*)* 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
• 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 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
• 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims 1
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
• CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims 1
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims 1
• 125000000719 pyrrolidinyl group Chemical group 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
• 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
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• 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
• 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
• 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
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• 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
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
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• 239000003054 catalyst Substances 0.000 description 8
• 239000013078 crystal Substances 0.000 description 8
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• 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
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• 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
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• 102000008946 Fibrinogen Human genes 0.000 description 6
• 238000003776 cleavage reaction Methods 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
• 230000007017 scission Effects 0.000 description 6
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• 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
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• 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
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• 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
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• 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
• 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
• 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 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
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