BG63237B2 - Производни на ароматен амид и негови соли - Google Patents
Производни на ароматен амид и негови соли Download PDFInfo
- Publication number
- BG63237B2 BG63237B2 BG098594A BG9859494A BG63237B2 BG 63237 B2 BG63237 B2 BG 63237B2 BG 098594 A BG098594 A BG 098594A BG 9859494 A BG9859494 A BG 9859494A BG 63237 B2 BG63237 B2 BG 63237B2
- Authority
- BG
- Bulgaria
- Prior art keywords
- ethyl
- phenyl
- nmr
- mixture
- pyrrolidinyl
- Prior art date
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- -1 of aromatic amidines Chemical class 0.000 title claims abstract description 205
- 150000003839 salts Chemical class 0.000 title claims description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 215
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 230000002265 prevention Effects 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 203
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 198
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 99
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 41
- 239000003795 chemical substances by application Substances 0.000 claims description 38
- 229920006395 saturated elastomer Polymers 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 208000007536 Thrombosis Diseases 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 239000003146 anticoagulant agent Substances 0.000 claims description 9
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 230000004087 circulation Effects 0.000 claims description 7
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 235000019260 propionic acid Nutrition 0.000 claims description 6
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 6
- 208000005189 Embolism Diseases 0.000 claims description 5
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 125000001589 carboacyl group Chemical group 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000005085 alkoxycarbonylalkoxy group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000005111 carboxyalkoxy group Chemical group 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 3
- AGRCGQSFFMCBRE-UXMRNZNESA-N 3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid Chemical compound C1N(C(=N)C)CC[C@@H]1OC1=CC=C(C(CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 AGRCGQSFFMCBRE-UXMRNZNESA-N 0.000 claims description 2
- 206010002388 Angina unstable Diseases 0.000 claims description 2
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 2
- 206010008132 Cerebral thrombosis Diseases 0.000 claims description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 2
- 208000010159 IgA glomerulonephritis Diseases 0.000 claims description 2
- 206010021263 IgA nephropathy Diseases 0.000 claims description 2
- 201000001429 Intracranial Thrombosis Diseases 0.000 claims description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 2
- 208000006193 Pulmonary infarction Diseases 0.000 claims description 2
- 208000007814 Unstable Angina Diseases 0.000 claims description 2
- 206010047249 Venous thrombosis Diseases 0.000 claims description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 2
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 2
- 230000015271 coagulation Effects 0.000 claims description 2
- 238000005345 coagulation Methods 0.000 claims description 2
- 238000007887 coronary angioplasty Methods 0.000 claims description 2
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 2
- 201000010849 intracranial embolism Diseases 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Chemical group 0.000 claims description 2
- 239000001301 oxygen Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 230000007575 pulmonary infarction Effects 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- MQAQKHCMPMBWIS-UKOKCHKQSA-N (2s)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;hydrochloride Chemical compound Cl.C1N(C(=N)C)CC[C@@H]1OC1=CC=C([C@H](CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 MQAQKHCMPMBWIS-UKOKCHKQSA-N 0.000 claims 1
- AGRCGQSFFMCBRE-UHFFFAOYSA-N 3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-(1-ethanimidoylpyrrolidin-3-yl)oxyphenyl]propanoic acid Chemical compound C1N(C(=N)C)CCC1OC1=CC=C(C(CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 AGRCGQSFFMCBRE-UHFFFAOYSA-N 0.000 claims 1
- 206010061216 Infarction Diseases 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 230000007574 infarction Effects 0.000 claims 1
- 210000004165 myocardium Anatomy 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 201000010875 transient cerebral ischemia Diseases 0.000 claims 1
- 230000002792 vascular Effects 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 71
- 238000000034 method Methods 0.000 abstract description 62
- 230000000694 effects Effects 0.000 abstract description 12
- 230000010100 anticoagulation Effects 0.000 abstract description 7
- 206010014523 Embolism and thrombosis Diseases 0.000 abstract description 4
- 230000023555 blood coagulation Effects 0.000 abstract description 2
- 230000006965 reversible inhibition Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 445
- 238000005160 1H NMR spectroscopy Methods 0.000 description 380
- 239000000243 solution Substances 0.000 description 365
- 239000000203 mixture Substances 0.000 description 338
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 217
- 239000002904 solvent Substances 0.000 description 199
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 191
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 180
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 166
- 230000000052 comparative effect Effects 0.000 description 160
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 156
- 238000003756 stirring Methods 0.000 description 146
- 239000007787 solid Substances 0.000 description 135
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 129
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 129
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 120
- 238000001816 cooling Methods 0.000 description 105
- 239000013078 crystal Substances 0.000 description 102
- 238000004440 column chromatography Methods 0.000 description 96
- 238000001914 filtration Methods 0.000 description 94
- 239000000741 silica gel Substances 0.000 description 93
- 229910002027 silica gel Inorganic materials 0.000 description 93
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 89
- 239000003480 eluent Substances 0.000 description 89
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 84
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 76
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 72
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 59
- 239000003921 oil Substances 0.000 description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- 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 56
- 239000012044 organic layer Substances 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 52
- FXSZGKYGUFCBQY-UHFFFAOYSA-N propanoic acid;dihydrochloride Chemical compound Cl.Cl.CCC(O)=O FXSZGKYGUFCBQY-UHFFFAOYSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- 238000004821 distillation Methods 0.000 description 46
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 42
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 39
- 238000010992 reflux Methods 0.000 description 39
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 35
- 238000010898 silica gel chromatography Methods 0.000 description 35
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 32
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 32
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 31
- 239000003054 catalyst Substances 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 27
- 238000010828 elution Methods 0.000 description 26
- 238000001035 drying Methods 0.000 description 23
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 22
- 239000002198 insoluble material Substances 0.000 description 22
- 229920000642 polymer Polymers 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 239000012312 sodium hydride Substances 0.000 description 22
- 229910000104 sodium hydride Inorganic materials 0.000 description 22
- 239000003463 adsorbent Substances 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- 229910021529 ammonia Inorganic materials 0.000 description 19
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 19
- 235000017557 sodium bicarbonate Nutrition 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- 239000011780 sodium chloride Substances 0.000 description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 18
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 18
- 239000005457 ice water Substances 0.000 description 17
- CHRJZRDFSQHIFI-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;styrene Chemical compound C=CC1=CC=CC=C1.C=CC1=CC=CC=C1C=C CHRJZRDFSQHIFI-UHFFFAOYSA-N 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000004007 reversed phase HPLC Methods 0.000 description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 14
- 238000001819 mass spectrum Methods 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 229910003445 palladium oxide Inorganic materials 0.000 description 14
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 14
- 230000008569 process Effects 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
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- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 10
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
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- VFECYOFFNUUXPX-UHFFFAOYSA-M (5-cyano-1-benzofuran-2-yl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].C=1C2=CC(C#N)=CC=C2OC=1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 VFECYOFFNUUXPX-UHFFFAOYSA-M 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
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- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- WGMHMVLZFAJNOT-UHFFFAOYSA-N 1-ethoxyethylideneazanium;chloride Chemical compound [Cl-].CCOC(C)=[NH2+] WGMHMVLZFAJNOT-UHFFFAOYSA-N 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 5
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
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- XBCIWLDUWWZGGL-UHFFFAOYSA-N [5-bromo-2-[2-(4-methoxyphenyl)ethyl]-1-benzofuran-3-yl]methanol Chemical compound C1=CC(OC)=CC=C1CCC1=C(CO)C2=CC(Br)=CC=C2O1 XBCIWLDUWWZGGL-UHFFFAOYSA-N 0.000 description 2
- CIIMINJBNNEBOC-UHFFFAOYSA-M [5-ethoxy-2-(3-ethoxy-3-oxopropyl)-4-methoxyphenyl]methyl-triphenylphosphanium;chloride Chemical compound [Cl-].CCOC(=O)CCC1=CC(OC)=C(OCC)C=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CIIMINJBNNEBOC-UHFFFAOYSA-M 0.000 description 2
- IHTYTYHXCRAMAV-UHFFFAOYSA-N acetic acid;dihydrochloride Chemical compound Cl.Cl.CC(O)=O IHTYTYHXCRAMAV-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
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- IDDXTZMJZVYAPP-UHFFFAOYSA-N benzhydryl 2-[2-(5-cyano-1-benzofuran-2-yl)ethenyl]-5-methoxybenzoate Chemical compound C=1C(OC)=CC=C(C=CC=2OC3=CC=C(C=C3C=2)C#N)C=1C(=O)OC(C=1C=CC=CC=1)C1=CC=CC=C1 IDDXTZMJZVYAPP-UHFFFAOYSA-N 0.000 description 2
- NIBGYBPCNXULOA-UHFFFAOYSA-N benzhydryl 2-formyl-5-methoxybenzoate Chemical compound COC1=CC=C(C=O)C(C(=O)OC(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NIBGYBPCNXULOA-UHFFFAOYSA-N 0.000 description 2
- KLQNJBAFEFFWQZ-UHFFFAOYSA-N benzoic acid;dihydrochloride Chemical compound Cl.Cl.OC(=O)C1=CC=CC=C1 KLQNJBAFEFFWQZ-UHFFFAOYSA-N 0.000 description 2
- OFULEGMRNRXCCQ-UHFFFAOYSA-N benzotriazol-1-yl 4-[2-(5-cyano-1-benzofuran-2-yl)ethyl]benzoate Chemical compound N#CC1=CC=C2OC(CCC3=CC=C(C=C3)C(ON3C4=CC=CC=C4N=N3)=O)=CC2=C1 OFULEGMRNRXCCQ-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000003114 blood coagulation factor Substances 0.000 description 2
- AJNWGKMIJZNIBI-UHFFFAOYSA-N butanoic acid;dihydrochloride Chemical compound Cl.Cl.CCCC(O)=O AJNWGKMIJZNIBI-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 2
- 239000004020 conductor Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 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 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- JNKCECILHVZKMB-UHFFFAOYSA-N diethyl 2-[4-(cyanomethoxy)phenyl]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)C1=CC=C(OCC#N)C=C1 JNKCECILHVZKMB-UHFFFAOYSA-N 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- NGJROWIAIGCUGO-UHFFFAOYSA-N ethyl 2-(2-acetyl-4-bromophenoxy)acetate Chemical compound CCOC(=O)COC1=CC=C(Br)C=C1C(C)=O NGJROWIAIGCUGO-UHFFFAOYSA-N 0.000 description 2
- DZBKHOWGZKCDNZ-UHFFFAOYSA-N ethyl 2-(4-acetyloxyphenyl)-3-(5-cyano-1-benzofuran-2-yl)prop-2-enoate Chemical compound C=1C2=CC(C#N)=CC=C2OC=1C=C(C(=O)OCC)C1=CC=C(OC(C)=O)C=C1 DZBKHOWGZKCDNZ-UHFFFAOYSA-N 0.000 description 2
- DZSXZYDBNQVSMU-UHFFFAOYSA-N ethyl 2-(4-hydroxyphenyl)-2-oxoacetate Chemical compound CCOC(=O)C(=O)C1=CC=C(O)C=C1 DZSXZYDBNQVSMU-UHFFFAOYSA-N 0.000 description 2
- VQTBETBFNSBCPZ-UHFFFAOYSA-N ethyl 2-[2-(5-cyano-1-benzofuran-2-yl)ethyl]-5-methoxybenzoate Chemical compound CCOC(=O)C1=CC(OC)=CC=C1CCC1=CC2=CC(C#N)=CC=C2O1 VQTBETBFNSBCPZ-UHFFFAOYSA-N 0.000 description 2
- IJAHYVTWXGELGG-UHFFFAOYSA-N ethyl 3-(4-ethoxy-3-methoxyphenyl)propanoate Chemical compound CCOC(=O)CCC1=CC=C(OCC)C(OC)=C1 IJAHYVTWXGELGG-UHFFFAOYSA-N 0.000 description 2
- YQVSDNKFMBSCDB-UHFFFAOYSA-N ethyl 3-(5-bromo-1-benzothiophen-2-yl)-2-(4-methoxyphenyl)propanoate Chemical compound C=1C2=CC(Br)=CC=C2SC=1CC(C(=O)OCC)C1=CC=C(OC)C=C1 YQVSDNKFMBSCDB-UHFFFAOYSA-N 0.000 description 2
- WVZDUXKGYGTJKS-UHFFFAOYSA-N ethyl 3-(5-cyano-1-benzothiophen-2-yl)-2-[4-[[2-[(4-nitrophenyl)methoxycarbonylamino]-1,4,5,6-tetrahydropyrimidin-5-yl]oxy]phenyl]propanoate Chemical compound C=1C2=CC(C#N)=CC=C2SC=1CC(C(=O)OCC)C(C=C1)=CC=C1OC(CN1)CNC1=NC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 WVZDUXKGYGTJKS-UHFFFAOYSA-N 0.000 description 2
- YLYAGXMAOLWCSE-VZBZPWRVSA-N ethyl 3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-pyrrolidin-3-yl]oxyphenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C=1C=C2C=CC(C(N)=N)=CC2=CC=1CC(C(=O)OCC)C(C=C1)=CC=C1O[C@H]1CCNC1 YLYAGXMAOLWCSE-VZBZPWRVSA-N 0.000 description 2
- VNRBNOJVGMORAE-UHFFFAOYSA-N ethyl 3-[2-[2-(5-cyano-1-benzothiophen-2-yl)ethyl]-4-ethoxy-5-methoxyphenyl]propanoate Chemical compound CCOC(=O)CCC1=CC(OC)=C(OCC)C=C1CCC1=CC2=CC(C#N)=CC=C2S1 VNRBNOJVGMORAE-UHFFFAOYSA-N 0.000 description 2
- QYNBPINLQQVHBJ-UHFFFAOYSA-N ethyl 5-bromo-1-benzothiophene-2-carboxylate Chemical compound BrC1=CC=C2SC(C(=O)OCC)=CC2=C1 QYNBPINLQQVHBJ-UHFFFAOYSA-N 0.000 description 2
- YGQHVWDPLQZPCH-UHFFFAOYSA-N ethyl 5-bromo-2-[2-(4-methoxyphenyl)ethyl]-1-benzofuran-3-carboxylate Chemical compound O1C2=CC=C(Br)C=C2C(C(=O)OCC)=C1CCC1=CC=C(OC)C=C1 YGQHVWDPLQZPCH-UHFFFAOYSA-N 0.000 description 2
- WJZILNCGMYSKQQ-UHFFFAOYSA-N ethyl 5-bromo-3-methyl-1-benzofuran-2-carboxylate Chemical compound C1=C(Br)C=C2C(C)=C(C(=O)OCC)OC2=C1 WJZILNCGMYSKQQ-UHFFFAOYSA-N 0.000 description 2
- GDKMBFBGOSPMPD-UHFFFAOYSA-N ethyl 5-bromo-7-methoxy-1-benzofuran-2-carboxylate Chemical compound BrC1=CC(OC)=C2OC(C(=O)OCC)=CC2=C1 GDKMBFBGOSPMPD-UHFFFAOYSA-N 0.000 description 2
- KURMBVGYOCYEDO-UHFFFAOYSA-N ethyl 5-cyano-1-benzothiophene-2-carboxylate Chemical compound N#CC1=CC=C2SC(C(=O)OCC)=CC2=C1 KURMBVGYOCYEDO-UHFFFAOYSA-N 0.000 description 2
- INBJYLZTAQYCDA-UHFFFAOYSA-N ethyl 5-cyano-7-methoxy-1-benzofuran-2-carboxylate Chemical compound N#CC1=CC(OC)=C2OC(C(=O)OCC)=CC2=C1 INBJYLZTAQYCDA-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- CLKNNHRMWYPHJN-UHFFFAOYSA-N methyl 2-oxo-2-[4-(oxolan-3-yloxy)phenyl]acetate Chemical compound C1=CC(C(=O)C(=O)OC)=CC=C1OC1COCC1 CLKNNHRMWYPHJN-UHFFFAOYSA-N 0.000 description 2
- CLKNNHRMWYPHJN-LLVKDONJSA-N methyl 2-oxo-2-[4-[(3r)-oxolan-3-yl]oxyphenyl]acetate Chemical compound C1=CC(C(=O)C(=O)OC)=CC=C1O[C@H]1COCC1 CLKNNHRMWYPHJN-LLVKDONJSA-N 0.000 description 2
- GCLKPEXDCMUCBA-KGPLAMFJSA-N methyl 3-(6-carbamimidoyl-1h-indol-2-yl)-2-[4-[(3s)-pyrrolidin-3-yl]oxyphenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C=1C2=CC=C(C(N)=N)C=C2NC=1CC(C(=O)OC)C(C=C1)=CC=C1O[C@H]1CCNC1 GCLKPEXDCMUCBA-KGPLAMFJSA-N 0.000 description 2
- SNUBOSDAWBWNGT-UHFFFAOYSA-N methyl 6-(oxan-2-yloxymethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate Chemical compound C1CC2=CC(C(=O)OC)=CC=C2CC1COC1CCCCO1 SNUBOSDAWBWNGT-UHFFFAOYSA-N 0.000 description 2
- XLFWJYAQDYMFMH-UHFFFAOYSA-N methyl 6-cyano-1-methylindole-2-carboxylate Chemical compound C1=C(C#N)C=C2N(C)C(C(=O)OC)=CC2=C1 XLFWJYAQDYMFMH-UHFFFAOYSA-N 0.000 description 2
- 229960001639 penicillamine Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- RKZDIVDEKBPOOV-UHFFFAOYSA-N s-(4-bromo-2-formylphenyl) n,n-dimethylcarbamothioate Chemical compound CN(C)C(=O)SC1=CC=C(Br)C=C1C=O RKZDIVDEKBPOOV-UHFFFAOYSA-N 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- MEQOYLKEHIWPOZ-AWEZNQCLSA-N tert-butyl (3s)-3-(4-formylphenoxy)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC1=CC=C(C=O)C=C1 MEQOYLKEHIWPOZ-AWEZNQCLSA-N 0.000 description 2
- PNADYHMMIBCXGZ-FHZUCYEKSA-N tert-butyl (3s)-3-[4-[1-(6-cyano-1h-indol-2-yl)-3-hydroxypropan-2-yl]phenoxy]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC1=CC=C(C(CO)CC=2NC3=CC(=CC=C3C=2)C#N)C=C1 PNADYHMMIBCXGZ-FHZUCYEKSA-N 0.000 description 2
- GVBXZOXXZYCGSC-QHCPKHFHSA-N tert-butyl (3s)-3-[4-[2-(5-cyano-1-benzofuran-2-yl)ethyl]phenoxy]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC(C=C1)=CC=C1CCC1=CC2=CC(C#N)=CC=C2O1 GVBXZOXXZYCGSC-QHCPKHFHSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
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- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- JAOZKJMVYIWLKU-UHFFFAOYSA-N sodium 7-hydroxy-8-[(4-sulfonaphthalen-1-yl)diazenyl]naphthalene-1,3-disulfonic acid Chemical compound C1=CC=C2C(=C1)C(=CC=C2S(=O)(=O)O)N=NC3=C(C=CC4=CC(=CC(=C43)S(=O)(=O)O)S(=O)(=O)O)O.[Na+] JAOZKJMVYIWLKU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- MXPOLUPSEVGAAS-VIFPVBQESA-N tert-butyl (2s)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1CCO MXPOLUPSEVGAAS-VIFPVBQESA-N 0.000 description 1
- FIIFEVCQBNLVEQ-GJZGRUSLSA-N tert-butyl (2s,4s)-2-carbamoyl-4-[4-(2-ethoxy-2-oxoacetyl)phenoxy]pyrrolidine-1-carboxylate Chemical compound C1=CC(C(=O)C(=O)OCC)=CC=C1O[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C1 FIIFEVCQBNLVEQ-GJZGRUSLSA-N 0.000 description 1
- KFIMLBTVCZDMIE-OAHLLOKOSA-N tert-butyl (3r)-3-[4-(2-ethoxy-2-oxoacetyl)phenoxy]pyrrolidine-1-carboxylate Chemical compound C1=CC(C(=O)C(=O)OCC)=CC=C1O[C@H]1CN(C(=O)OC(C)(C)C)CC1 KFIMLBTVCZDMIE-OAHLLOKOSA-N 0.000 description 1
- KFIMLBTVCZDMIE-HNNXBMFYSA-N tert-butyl (3s)-3-[4-(2-ethoxy-2-oxoacetyl)phenoxy]pyrrolidine-1-carboxylate Chemical compound C1=CC(C(=O)C(=O)OCC)=CC=C1O[C@@H]1CN(C(=O)OC(C)(C)C)CC1 KFIMLBTVCZDMIE-HNNXBMFYSA-N 0.000 description 1
- IIQPTLXCZNENJR-QFIPXVFZSA-N tert-butyl (3s)-3-[4-[2-(5-cyano-3-ethoxycarbonyl-1-benzofuran-2-yl)ethyl]phenoxy]pyrrolidine-1-carboxylate Chemical compound O1C2=CC=C(C#N)C=C2C(C(=O)OCC)=C1CCC(C=C1)=CC=C1O[C@H]1CCN(C(=O)OC(C)(C)C)C1 IIQPTLXCZNENJR-QFIPXVFZSA-N 0.000 description 1
- CRQLZHDHPMPKCC-QHCPKHFHSA-N tert-butyl (3s)-3-[4-[2-(6-cyano-1h-indol-2-yl)ethenyl]phenoxy]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC(C=C1)=CC=C1C=CC1=CC2=CC=C(C#N)C=C2N1 CRQLZHDHPMPKCC-QHCPKHFHSA-N 0.000 description 1
- FPWSVALUFXHANF-QHCPKHFHSA-N tert-butyl (3s)-3-[4-[2-(6-cyano-1h-indol-2-yl)ethyl]phenoxy]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC(C=C1)=CC=C1CCC1=CC2=CC=C(C#N)C=C2N1 FPWSVALUFXHANF-QHCPKHFHSA-N 0.000 description 1
- JKILWXBEDIAENW-QHCPKHFHSA-N tert-butyl (3s)-3-[4-[3-(5-cyano-1-benzofuran-3-yl)propyl]phenoxy]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC(C=C1)=CC=C1CCCC1=COC2=CC=C(C#N)C=C12 JKILWXBEDIAENW-QHCPKHFHSA-N 0.000 description 1
- HMHRSWLVFVDTEY-UXMRNZNESA-N tert-butyl (3s)-3-[4-[3-(5-cyano-1h-indol-2-yl)-1-methoxy-1-oxopropan-2-yl]phenoxy]pyrrolidine-1-carboxylate Chemical compound C=1C2=CC(C#N)=CC=C2NC=1CC(C(=O)OC)C(C=C1)=CC=C1O[C@H]1CCN(C(=O)OC(C)(C)C)C1 HMHRSWLVFVDTEY-UXMRNZNESA-N 0.000 description 1
- IDEXYXDWJGAYTN-UHFFFAOYSA-N tert-butyl 4-[4-[(5-cyano-1-benzofuran-2-yl)methyl]phenoxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC(C=C1)=CC=C1CC1=CC2=CC(C#N)=CC=C2O1 IDEXYXDWJGAYTN-UHFFFAOYSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- QQWYQAQQADNEIC-UHFFFAOYSA-N tert-butyl [[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)ON=C(C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-UHFFFAOYSA-N 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LQRGWGOFPUXNOV-SSDOTTSWSA-N tert-butyl n-[(2r)-1-hydroxybutan-2-yl]carbamate Chemical compound CC[C@H](CO)NC(=O)OC(C)(C)C LQRGWGOFPUXNOV-SSDOTTSWSA-N 0.000 description 1
- FXMNVYBROILAKU-UHFFFAOYSA-N tert-butyl n-[cyano(phenyl)methylidene]carbamate Chemical compound CC(C)(C)OC(=O)N=C(C#N)C1=CC=CC=C1 FXMNVYBROILAKU-UHFFFAOYSA-N 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- CUPOOAWTRIURFT-UHFFFAOYSA-N thiophene-2-carbonitrile Chemical compound N#CC1=CC=CS1 CUPOOAWTRIURFT-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
-
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
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- Hydrogenated Pyridines (AREA)
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Application Number | Priority Date | Filing Date | Title |
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JP28608891 | 1991-10-31 |
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BG098594A BG63237B2 (bg) | 1991-10-31 | 1994-02-25 | Производни на ароматен амид и негови соли |
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US (4) | US5576343A (zh) |
EP (1) | EP0540051B1 (zh) |
JP (2) | JP2879718B2 (zh) |
KR (1) | KR100205152B1 (zh) |
CN (3) | CN1049434C (zh) |
AT (1) | ATE136293T1 (zh) |
AU (1) | AU666137B2 (zh) |
BG (1) | BG63237B2 (zh) |
CA (1) | CA2081836C (zh) |
CZ (1) | CZ284381B6 (zh) |
DE (1) | DE69209615T2 (zh) |
DK (1) | DK0540051T3 (zh) |
EE (1) | EE03024B1 (zh) |
ES (1) | ES2088073T3 (zh) |
FI (1) | FI107923B (zh) |
GR (1) | GR3019832T3 (zh) |
HK (1) | HK1002999A1 (zh) |
HR (1) | HRP921147B1 (zh) |
HU (1) | HU221976B1 (zh) |
IL (1) | IL103564A (zh) |
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NZ (1) | NZ244936A (zh) |
PL (1) | PL170312B1 (zh) |
RU (1) | RU2139851C1 (zh) |
SG (1) | SG78251A1 (zh) |
SK (1) | SK327692A3 (zh) |
TW (1) | TW210998B (zh) |
ZA (1) | ZA928276B (zh) |
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US5256812A (en) * | 1989-01-31 | 1993-10-26 | Hoffmann-La Roche Inc. | Carboxamides and sulfonamides |
US4952562A (en) * | 1989-09-29 | 1990-08-28 | Rorer Pharmaceutical Corporation | Anti-thrombotic peptides and pseudopeptides |
US5258398A (en) * | 1991-12-16 | 1993-11-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Antithrombotic diaminoalkanoic acid derivatives |
JPH08176139A (ja) * | 1994-12-20 | 1996-07-09 | Tokuyama Corp | クロメン化合物 |
-
1992
- 1992-10-26 ZA ZA928276A patent/ZA928276B/xx unknown
- 1992-10-27 IL IL10356492A patent/IL103564A/en not_active IP Right Cessation
- 1992-10-28 TW TW081108599A patent/TW210998B/zh active
- 1992-10-29 NO NO924164A patent/NO302948B1/no unknown
- 1992-10-29 HR HRHEI-3-286088A patent/HRP921147B1/xx not_active IP Right Cessation
- 1992-10-29 NZ NZ244936A patent/NZ244936A/en not_active IP Right Cessation
- 1992-10-30 SG SG1996006031A patent/SG78251A1/en unknown
- 1992-10-30 CZ CS923276A patent/CZ284381B6/cs not_active IP Right Cessation
- 1992-10-30 MX MX9206295A patent/MX9206295A/es not_active IP Right Cessation
- 1992-10-30 DE DE69209615T patent/DE69209615T2/de not_active Expired - Fee Related
- 1992-10-30 HU HU9203433A patent/HU221976B1/hu not_active IP Right Cessation
- 1992-10-30 FI FI924932A patent/FI107923B/fi not_active IP Right Cessation
- 1992-10-30 DK DK92118705.0T patent/DK0540051T3/da active
- 1992-10-30 JP JP4292892A patent/JP2879718B2/ja not_active Expired - Fee Related
- 1992-10-30 AT AT92118705T patent/ATE136293T1/de not_active IP Right Cessation
- 1992-10-30 SK SK3276-92A patent/SK327692A3/sk unknown
- 1992-10-30 EP EP92118705A patent/EP0540051B1/en not_active Expired - Lifetime
- 1992-10-30 ES ES92118705T patent/ES2088073T3/es not_active Expired - Lifetime
- 1992-10-30 PL PL92296439A patent/PL170312B1/pl not_active IP Right Cessation
- 1992-10-30 AU AU27470/92A patent/AU666137B2/en not_active Ceased
- 1992-10-30 CA CA002081836A patent/CA2081836C/en not_active Expired - Fee Related
- 1992-10-30 RU RU92004542A patent/RU2139851C1/ru not_active IP Right Cessation
- 1992-10-31 KR KR1019920020309A patent/KR100205152B1/ko not_active IP Right Cessation
- 1992-10-31 CN CN92114304A patent/CN1049434C/zh not_active Expired - Fee Related
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1994
- 1994-02-25 BG BG098594A patent/BG63237B2/bg unknown
- 1994-11-22 EE EE9400407A patent/EE03024B1/xx not_active IP Right Cessation
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1995
- 1995-06-06 US US08/468,304 patent/US5576343A/en not_active Expired - Fee Related
- 1995-06-06 US US08/471,173 patent/US5620991A/en not_active Expired - Fee Related
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1996
- 1996-05-06 GR GR960401207T patent/GR3019832T3/el unknown
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1997
- 1997-04-16 CN CN97110745A patent/CN1097052C/zh not_active Expired - Fee Related
- 1997-04-16 CN CN97110748A patent/CN1062865C/zh not_active Expired - Fee Related
- 1997-09-05 US US08/924,504 patent/US5866577A/en not_active Expired - Fee Related
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1998
- 1998-03-12 HK HK98102072A patent/HK1002999A1/xx not_active IP Right Cessation
- 1998-03-31 JP JP08545498A patent/JP3461441B2/ja not_active Expired - Fee Related
- 1998-08-07 US US09/131,235 patent/US5962695A/en not_active Expired - Fee Related
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