BG105986A - Пролекарства на тромбинови инхибитори - Google Patents

Пролекарства на тромбинови инхибитори Download PDF

Info

Publication number: BG105986A
Authority: BG; Bulgaria
Prior art keywords: alkyl; cycloalkyl; ooc; radicals; phenyl
Prior art date: 1999-04-09

Application number

BG105986A

Other languages

Bulgarian (bg)

English (en)

Inventor

Dorit Baucke

Helmut Mack

Werner Seitz

Wilfried Hornberger

Gisela Backfisch

Juergen DELZER

Original Assignee

Abbott Gmbh & Co. Kg

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1999-04-09

Filing date

2001-10-05

Publication date

2002-06-28

2001-10-05 Application filed by Abbott Gmbh & Co. Kg filed Critical Abbott Gmbh & Co. Kg

2002-06-28 Publication of BG105986A publication Critical patent/BG105986A/bg

Links

229940002612 prodrug Drugs 0.000 title claims abstract description 20
239000000651 prodrug Substances 0.000 title claims abstract description 20
229940122388 Thrombin inhibitor Drugs 0.000 title abstract description 12
239000003868 thrombin inhibitor Substances 0.000 title abstract description 12
-1 heterocyclic amidines Chemical class 0.000 claims abstract description 260
150000001875 compounds Chemical class 0.000 claims abstract description 112
238000002360 preparation method Methods 0.000 claims abstract description 68
108090000190 Thrombin Proteins 0.000 claims abstract description 39
229960004072 thrombin Drugs 0.000 claims abstract description 38
239000003814 drug Substances 0.000 claims abstract description 18
125000000217 alkyl group Chemical group 0.000 claims description 77
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 67
125000003118 aryl group Chemical group 0.000 claims description 46
229910052801 chlorine Inorganic materials 0.000 claims description 46
229910052799 carbon Inorganic materials 0.000 claims description 43
125000000753 cycloalkyl group Chemical group 0.000 claims description 41
229910052739 hydrogen Inorganic materials 0.000 claims description 41
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
150000001602 bicycloalkyls Chemical group 0.000 claims description 21
125000000000 cycloalkoxy group Chemical group 0.000 claims description 16
239000002253 acid Substances 0.000 claims description 14
239000001257 hydrogen Substances 0.000 claims description 14
150000003839 salts Chemical class 0.000 claims description 13
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
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 11
230000001419 dependent effect Effects 0.000 claims description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
238000011282 treatment Methods 0.000 claims description 11
125000003545 alkoxy group Chemical group 0.000 claims description 10
210000004027 cell Anatomy 0.000 claims description 7
210000001035 gastrointestinal tract Anatomy 0.000 claims description 7
125000006414 CCl Chemical group ClC* 0.000 claims description 6
238000010521 absorption reaction Methods 0.000 claims description 6
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
230000007246 mechanism Effects 0.000 claims description 6
229910052760 oxygen Inorganic materials 0.000 claims description 6
125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 6
230000036470 plasma concentration Effects 0.000 claims description 6
230000002265 prevention Effects 0.000 claims description 6
229910052717 sulfur Inorganic materials 0.000 claims description 6
125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 6
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
208000005189 Embolism Diseases 0.000 claims description 5
125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 5
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 5
230000001575 pathological effect Effects 0.000 claims description 5
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
150000007513 acids Chemical class 0.000 claims description 4
230000009471 action Effects 0.000 claims description 4
125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 claims description 4
125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 4
210000000329 smooth muscle myocyte Anatomy 0.000 claims description 4
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 4
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
206010027476 Metastases Diseases 0.000 claims description 3
238000009825 accumulation Methods 0.000 claims description 3
230000004663 cell proliferation Effects 0.000 claims description 3
208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 3
150000002431 hydrogen Chemical class 0.000 claims description 3
230000009401 metastasis Effects 0.000 claims description 3
230000035699 permeability Effects 0.000 claims description 3
230000002797 proteolythic effect Effects 0.000 claims description 3
230000010410 reperfusion Effects 0.000 claims description 3
208000037803 restenosis Diseases 0.000 claims description 3
229960000103 thrombolytic agent Drugs 0.000 claims description 3
230000002537 thrombolytic effect Effects 0.000 claims description 3
210000004881 tumor cell Anatomy 0.000 claims description 3
230000004913 activation Effects 0.000 claims description 2
230000004075 alteration Effects 0.000 claims description 2
238000011278 co-treatment Methods 0.000 claims description 2
210000002919 epithelial cell Anatomy 0.000 claims description 2
230000014509 gene expression Effects 0.000 claims description 2
230000005764 inhibitory process Effects 0.000 claims description 2
230000002297 mitogenic effect Effects 0.000 claims description 2
238000007911 parenteral administration Methods 0.000 claims description 2
GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 claims description 2
239000000546 pharmaceutical excipient Substances 0.000 claims description 2
108020003175 receptors Proteins 0.000 claims description 2
102000005962 receptors Human genes 0.000 claims description 2
230000009467 reduction Effects 0.000 claims description 2
230000019491 signal transduction Effects 0.000 claims description 2
230000000638 stimulation Effects 0.000 claims description 2
230000004614 tumor growth Effects 0.000 claims description 2
229910052727 yttrium Inorganic materials 0.000 claims description 2
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
125000006519 CCH3 Chemical group 0.000 claims 1
229910003844 NSO2 Inorganic materials 0.000 claims 1
239000012050 conventional carrier Substances 0.000 claims 1
108060005987 Kallikrein Proteins 0.000 abstract description 3
102000001399 Kallikrein Human genes 0.000 abstract description 3
239000003146 anticoagulant agent Substances 0.000 abstract description 3
229940127219 anticoagulant drug Drugs 0.000 abstract description 3
239000003112 inhibitor Substances 0.000 abstract description 3
239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
229940121363 anti-inflammatory agent Drugs 0.000 abstract description 2
230000002860 competitive effect Effects 0.000 abstract description 2
238000001727 in vivo Methods 0.000 abstract description 2
239000008194 pharmaceutical composition Substances 0.000 abstract description 2
MTCFGRXMJLQNBG-UHFFFAOYSA-N serine Chemical compound OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 abstract 2
108091005804 Peptidases Proteins 0.000 abstract 1
102000035195 Peptidases Human genes 0.000 abstract 1
239000004365 Protease Substances 0.000 abstract 1
241001522306 Serinus serinus Species 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 414
239000000243 solution Substances 0.000 description 206
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 202
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 198
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 198
YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 195
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
229930192474 thiophene Natural products 0.000 description 124
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 89
239000000047 product Substances 0.000 description 79
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 78
150000003254 radicals Chemical class 0.000 description 77
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 74
239000000203 mixture Substances 0.000 description 67
239000007787 solid Substances 0.000 description 65
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 63
239000002904 solvent Substances 0.000 description 60
238000006243 chemical reaction Methods 0.000 description 59
238000003756 stirring Methods 0.000 description 59
239000011541 reaction mixture Substances 0.000 description 57
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
125000006239 protecting group Chemical group 0.000 description 54
239000012043 crude product Substances 0.000 description 53
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 47
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 46
239000012074 organic phase Substances 0.000 description 44
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
229910052943 magnesium sulfate Inorganic materials 0.000 description 39
235000019341 magnesium sulphate Nutrition 0.000 description 39
238000005160 1H NMR spectroscopy Methods 0.000 description 33
230000032050 esterification Effects 0.000 description 33
238000005886 esterification reaction Methods 0.000 description 33
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
238000004440 column chromatography Methods 0.000 description 32
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 32
229910000041 hydrogen chloride Inorganic materials 0.000 description 32
238000000746 purification Methods 0.000 description 32
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 31
VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
239000003921 oil Substances 0.000 description 31
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 30
238000005809 transesterification reaction Methods 0.000 description 29
239000000460 chlorine Substances 0.000 description 27
239000012071 phase Substances 0.000 description 25
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
239000000843 powder Substances 0.000 description 24
229920006395 saturated elastomer Polymers 0.000 description 22
OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical compound OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 description 21
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 21
238000001816 cooling Methods 0.000 description 21
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 20
239000008346 aqueous phase Substances 0.000 description 20
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 20
239000000126 substance Substances 0.000 description 20
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
239000000725 suspension Substances 0.000 description 19
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
230000006870 function Effects 0.000 description 18
239000002244 precipitate Substances 0.000 description 18
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 18
238000001035 drying Methods 0.000 description 17
239000000741 silica gel Substances 0.000 description 17
229910002027 silica gel Inorganic materials 0.000 description 17
229910052938 sodium sulfate Inorganic materials 0.000 description 17
235000011152 sodium sulphate Nutrition 0.000 description 17
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
230000015572 biosynthetic process Effects 0.000 description 15
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 15
238000004809 thin layer chromatography Methods 0.000 description 15
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 14
229960000583 acetic acid Drugs 0.000 description 14
RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 13
229910021529 ammonia Inorganic materials 0.000 description 13
230000035602 clotting Effects 0.000 description 13
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 12
OXCZROVJFNJEGL-UHFFFAOYSA-N NCC1=NC(C(NO)=N)=CS1.Cl Chemical compound NCC1=NC(C(NO)=N)=CS1.Cl OXCZROVJFNJEGL-UHFFFAOYSA-N 0.000 description 12
238000001914 filtration Methods 0.000 description 12
229910000037 hydrogen sulfide Inorganic materials 0.000 description 12
239000003208 petroleum Substances 0.000 description 12
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
238000003786 synthesis reaction Methods 0.000 description 12
239000003456 ion exchange resin Substances 0.000 description 11
229920003303 ion-exchange polymer Polymers 0.000 description 11
238000000034 method Methods 0.000 description 11
238000012360 testing method Methods 0.000 description 11
NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 10
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
229940079593 drug Drugs 0.000 description 10
239000000706 filtrate Substances 0.000 description 10
239000007789 gas Substances 0.000 description 10
HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 10
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 10
235000001014 amino acid Nutrition 0.000 description 9
238000005859 coupling reaction Methods 0.000 description 9
238000010511 deprotection reaction Methods 0.000 description 9
239000002274 desiccant Substances 0.000 description 9
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
238000004128 high performance liquid chromatography Methods 0.000 description 9
229910052757 nitrogen Inorganic materials 0.000 description 9
XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 9
230000008878 coupling Effects 0.000 description 8
238000010168 coupling process Methods 0.000 description 8
WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 8
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 7
206010053567 Coagulopathies Diseases 0.000 description 7
102000009123 Fibrin Human genes 0.000 description 7
108010073385 Fibrin Proteins 0.000 description 7
BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 7
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 7
238000004821 distillation Methods 0.000 description 7
229950003499 fibrin Drugs 0.000 description 7
229910000342 sodium bisulfate Inorganic materials 0.000 description 7
239000012312 sodium hydride Substances 0.000 description 7
229910000104 sodium hydride Inorganic materials 0.000 description 7
239000007858 starting material Substances 0.000 description 7
TVPJJKGFBGKYGU-UHFFFAOYSA-N 2-(aminomethyl)-1,3-thiazole-4-carbonitrile Chemical compound NCC1=NC(C#N)=CS1 TVPJJKGFBGKYGU-UHFFFAOYSA-N 0.000 description 6
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
229910004373 HOAc Inorganic materials 0.000 description 6
AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 6
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
230000029936 alkylation Effects 0.000 description 6
238000005804 alkylation reaction Methods 0.000 description 6
150000001413 amino acids Chemical class 0.000 description 6
235000011114 ammonium hydroxide Nutrition 0.000 description 6
239000008280 blood Substances 0.000 description 6
210000004369 blood Anatomy 0.000 description 6
239000003153 chemical reaction reagent Substances 0.000 description 6
PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 6
208000035475 disorder Diseases 0.000 description 6
239000003480 eluent Substances 0.000 description 6
ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 6
229910000027 potassium carbonate Inorganic materials 0.000 description 6
238000010992 reflux Methods 0.000 description 6
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
239000005695 Ammonium acetate Substances 0.000 description 5
238000003820 Medium-pressure liquid chromatography Methods 0.000 description 5
108010000499 Thromboplastin Proteins 0.000 description 5
102000002262 Thromboplastin Human genes 0.000 description 5
235000019257 ammonium acetate Nutrition 0.000 description 5
229940043376 ammonium acetate Drugs 0.000 description 5
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
230000023555 blood coagulation Effects 0.000 description 5
238000004587 chromatography analysis Methods 0.000 description 5
229940043279 diisopropylamine Drugs 0.000 description 5
230000000694 effects Effects 0.000 description 5
150000002148 esters Chemical group 0.000 description 5
238000001704 evaporation Methods 0.000 description 5
230000008020 evaporation Effects 0.000 description 5
238000003818 flash chromatography Methods 0.000 description 5
239000000543 intermediate Substances 0.000 description 5
230000004060 metabolic process Effects 0.000 description 5
125000001424 substituent group Chemical group 0.000 description 5
PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 4
PEXSOFOODHTMGT-UHFFFAOYSA-N 2-(aminomethyl)-N'-hydroxy-1,3-thiazole-4-carboximidamide Chemical compound C1=C(N=C(S1)CN)C(=NO)N PEXSOFOODHTMGT-UHFFFAOYSA-N 0.000 description 4
LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 4
VGVHNLRUAMRIEW-UHFFFAOYSA-N 4-methylcyclohexan-1-one Chemical compound CC1CCC(=O)CC1 VGVHNLRUAMRIEW-UHFFFAOYSA-N 0.000 description 4
OSDGTEZAPBYUQX-UHFFFAOYSA-N 5-(aminomethyl)thiophene-3-carbonitrile Chemical compound NCC1=CC(C#N)=CS1 OSDGTEZAPBYUQX-UHFFFAOYSA-N 0.000 description 4
GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 4
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
150000001299 aldehydes Chemical group 0.000 description 4
150000001409 amidines Chemical class 0.000 description 4
239000007864 aqueous solution Substances 0.000 description 4
ORQXBVXKBGUSBA-UHFFFAOYSA-N cyclohexyl D-alanine Natural products OC(=O)C(N)CC1CCCCC1 ORQXBVXKBGUSBA-UHFFFAOYSA-N 0.000 description 4
239000000284 extract Substances 0.000 description 4
239000006260 foam Substances 0.000 description 4
238000001990 intravenous administration Methods 0.000 description 4
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
238000004007 reversed phase HPLC Methods 0.000 description 4
238000000926 separation method Methods 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 3
AAKPCYMLWQWJBM-UHFFFAOYSA-N 2-(1,3-thiazol-2-ylmethyl)guanidine Chemical compound NC(N)=NCC1=NC=CS1 AAKPCYMLWQWJBM-UHFFFAOYSA-N 0.000 description 3
MQDDEDLGFFIARJ-UHFFFAOYSA-N 2-(thiophen-2-ylmethyl)guanidine;hydrochloride Chemical compound Cl.NC(N)=NCC1=CC=CS1 MQDDEDLGFFIARJ-UHFFFAOYSA-N 0.000 description 3
YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
ZAQXSMCYFQJRCQ-UHFFFAOYSA-N 3-(1-adamantyl)-2-azaniumylpropanoate Chemical compound C1C(C2)CC3CC2CC1(CC(N)C(O)=O)C3 ZAQXSMCYFQJRCQ-UHFFFAOYSA-N 0.000 description 3
SCBOWDZUPXXCOQ-UHFFFAOYSA-N 4-formylthiophene-2-carbonitrile Chemical compound O=CC1=CSC(C#N)=C1 SCBOWDZUPXXCOQ-UHFFFAOYSA-N 0.000 description 3
WDSOCAIUQQRVFQ-UHFFFAOYSA-N 5-(aminomethyl)thiophene-3-carbonitrile;hydrochloride Chemical compound Cl.NCC1=CC(C#N)=CS1 WDSOCAIUQQRVFQ-UHFFFAOYSA-N 0.000 description 3
RFQAZQHGFPGMSU-UHFFFAOYSA-N 5-(chloromethyl)-1,2-oxazole-3-carboxylic acid Chemical compound OC(=O)C=1C=C(CCl)ON=1 RFQAZQHGFPGMSU-UHFFFAOYSA-N 0.000 description 3
ZKLBPUYMTHPNOQ-UHFFFAOYSA-N 5-bromothiophene-3-carbaldehyde Chemical compound BrC1=CC(C=O)=CS1 ZKLBPUYMTHPNOQ-UHFFFAOYSA-N 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
PQVLDLROEAKSBH-UHFFFAOYSA-N CONC(C1=CSC(CN)=C1)=N.Cl Chemical compound CONC(C1=CSC(CN)=C1)=N.Cl PQVLDLROEAKSBH-UHFFFAOYSA-N 0.000 description 3
XDNNBOFCVPZYGZ-UHFFFAOYSA-N CONC(C1=CSC(CN)=N1)=N.Cl Chemical compound CONC(C1=CSC(CN)=N1)=N.Cl XDNNBOFCVPZYGZ-UHFFFAOYSA-N 0.000 description 3
239000004471 Glycine Substances 0.000 description 3
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
150000001242 acetic acid derivatives Chemical class 0.000 description 3
239000013543 active substance Substances 0.000 description 3
125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
235000019270 ammonium chloride Nutrition 0.000 description 3
238000004458 analytical method Methods 0.000 description 3
150000008064 anhydrides Chemical class 0.000 description 3
230000002785 anti-thrombosis Effects 0.000 description 3
230000008901 benefit Effects 0.000 description 3
125000004432 carbon atom Chemical group C* 0.000 description 3
238000002425 crystallisation Methods 0.000 description 3
230000008025 crystallization Effects 0.000 description 3
KWADKXWQVLDXEI-UHFFFAOYSA-N ethyl 2-formamidoprop-2-enoate Chemical class CCOC(=O)C(=C)NC=O KWADKXWQVLDXEI-UHFFFAOYSA-N 0.000 description 3
238000002474 experimental method Methods 0.000 description 3
238000000605 extraction Methods 0.000 description 3
239000012362 glacial acetic acid Substances 0.000 description 3
BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
150000002576 ketones Chemical group 0.000 description 3
239000012528 membrane Substances 0.000 description 3
XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 3
239000002480 mineral oil Substances 0.000 description 3
235000010446 mineral oil Nutrition 0.000 description 3
150000002825 nitriles Chemical group 0.000 description 3
125000004430 oxygen atom Chemical group O* 0.000 description 3
239000011734 sodium Substances 0.000 description 3
239000012279 sodium borohydride Substances 0.000 description 3
229910000033 sodium borohydride Inorganic materials 0.000 description 3
239000011780 sodium chloride Substances 0.000 description 3
239000011593 sulfur Chemical group 0.000 description 3
BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 3
KJIOQYGWTQBHNH-UHFFFAOYSA-N undecanol Chemical compound CCCCCCCCCCCO KJIOQYGWTQBHNH-UHFFFAOYSA-N 0.000 description 3
WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 2
125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 2
AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 2
FXZFFVCJWZTTMX-UHFFFAOYSA-N 1-methylcyclohexane-1-carbaldehyde Chemical compound O=CC1(C)CCCCC1 FXZFFVCJWZTTMX-UHFFFAOYSA-N 0.000 description 2
OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 2
KKFAAUVAMMLJDF-UHFFFAOYSA-N 2-(aminomethyl)-1,3-thiazole-4-carbothioamide Chemical compound NCC1=NC(C(N)=S)=CS1 KKFAAUVAMMLJDF-UHFFFAOYSA-N 0.000 description 2
AGOHDFKCSLZSSL-UHFFFAOYSA-N 2-(aminomethyl)-4-(trifluoromethyl)-1,3-thiazole-5-carboximidamide Chemical compound NCC1=NC(C(F)(F)F)=C(C(N)=N)S1 AGOHDFKCSLZSSL-UHFFFAOYSA-N 0.000 description 2
YBTXCPKMVLYQTQ-UHFFFAOYSA-N 2-(aminomethyl)-4-methyl-1,3-thiazole-5-carboximidamide Chemical compound CC=1N=C(CN)SC=1C(N)=N YBTXCPKMVLYQTQ-UHFFFAOYSA-N 0.000 description 2
NPLBBQAAYSJEMO-UHFFFAOYSA-N 2-(cycloheptylazaniumyl)acetate Chemical compound OC(=O)CNC1CCCCCC1 NPLBBQAAYSJEMO-UHFFFAOYSA-N 0.000 description 2
PNKNDNFLQNMQJL-UHFFFAOYSA-N 2-(cyclooctylazaniumyl)acetate Chemical compound OC(=O)CNC1CCCCCCC1 PNKNDNFLQNMQJL-UHFFFAOYSA-N 0.000 description 2
LRHRHAWNXCGABU-UHFFFAOYSA-N 2-(cyclopentylazaniumyl)acetate Chemical compound OC(=O)CNC1CCCC1 LRHRHAWNXCGABU-UHFFFAOYSA-N 0.000 description 2
XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
YXDXXGXWFJCXEB-UHFFFAOYSA-N 2-furonitrile Chemical compound N#CC1=CC=CO1 YXDXXGXWFJCXEB-UHFFFAOYSA-N 0.000 description 2
QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 description 2
ZVJQBBYAVPAFLX-UHFFFAOYSA-N 3,3-dimethylcyclohexan-1-one Chemical compound CC1(C)CCCC(=O)C1 ZVJQBBYAVPAFLX-UHFFFAOYSA-N 0.000 description 2
TUXUBPZOTSIPJA-UHFFFAOYSA-N 3,3-dimethylcyclohexane-1-carbaldehyde Chemical compound CC1(C)CCCC(C=O)C1 TUXUBPZOTSIPJA-UHFFFAOYSA-N 0.000 description 2
XUWKRXZHYHXSBI-UHFFFAOYSA-N 3-(bromomethyl)thiophene-2-carbonitrile Chemical compound BrCC=1C=CSC=1C#N XUWKRXZHYHXSBI-UHFFFAOYSA-N 0.000 description 2
MZUHMRDGJUBYAU-UHFFFAOYSA-N 3-(hydroxymethyl)thiophene-2-carbonitrile Chemical compound OCC=1C=CSC=1C#N MZUHMRDGJUBYAU-UHFFFAOYSA-N 0.000 description 2
WBYYMMBGRPQRSD-UHFFFAOYSA-N 4-(chloromethyl)-1,3-thiazole-2-carboxamide Chemical compound NC(=O)C1=NC(CCl)=CS1 WBYYMMBGRPQRSD-UHFFFAOYSA-N 0.000 description 2
VJLXRRTVABNKJA-UHFFFAOYSA-N 4-chloro-5-(hydroxymethyl)thiophene-3-carbonitrile Chemical compound OCC=1SC=C(C#N)C=1Cl VJLXRRTVABNKJA-UHFFFAOYSA-N 0.000 description 2
BVFSVQRHFKTEMM-UHFFFAOYSA-N 4-chloro-5-formylthiophene-3-carbonitrile Chemical compound ClC1=C(C=O)SC=C1C#N BVFSVQRHFKTEMM-UHFFFAOYSA-N 0.000 description 2
IFKSGHLMAKRHQQ-UHFFFAOYSA-N 5-(aminomethyl)-1,2,4-oxadiazole-3-carbonitrile;hydrochloride Chemical compound Cl.NCC1=NC(C#N)=NO1 IFKSGHLMAKRHQQ-UHFFFAOYSA-N 0.000 description 2
VYSCDLZIYMYEOY-UHFFFAOYSA-N 5-(aminomethyl)-3-methylthiophene-2-carbonitrile Chemical compound CC=1C=C(CN)SC=1C#N VYSCDLZIYMYEOY-UHFFFAOYSA-N 0.000 description 2
ZSHWHOXETLPOKC-UHFFFAOYSA-N 5-(aminomethyl)-4-methylthiophene-3-carbothioamide Chemical compound CC1=C(CN)SC=C1C(N)=S ZSHWHOXETLPOKC-UHFFFAOYSA-N 0.000 description 2
HACNLSKAWWXFEW-UHFFFAOYSA-N 5-(aminomethyl)-N'-hydroxythiophene-3-carboximidamide Chemical compound C1=C(SC=C1C(=NO)N)CN HACNLSKAWWXFEW-UHFFFAOYSA-N 0.000 description 2
YSOBWORYTNVBAV-UHFFFAOYSA-N 5-(aminomethyl)furan-3-carbonitrile;hydrochloride Chemical compound Cl.NCC1=CC(C#N)=CO1 YSOBWORYTNVBAV-UHFFFAOYSA-N 0.000 description 2
FHYNZXSHHPBOBK-UHFFFAOYSA-N 5-(aminomethyl)thiophene-2-carbonitrile Chemical compound NCC1=CC=C(C#N)S1 FHYNZXSHHPBOBK-UHFFFAOYSA-N 0.000 description 2
LYBHGFYIJPQIKP-UHFFFAOYSA-N 5-(bromomethyl)-3-methylthiophene-2-carbonitrile Chemical compound CC=1C=C(CBr)SC=1C#N LYBHGFYIJPQIKP-UHFFFAOYSA-N 0.000 description 2
AZVCRELZXHPNJG-UHFFFAOYSA-N 5-(bromomethyl)-4-chlorothiophene-3-carbonitrile Chemical compound ClC1=C(CBr)SC=C1C#N AZVCRELZXHPNJG-UHFFFAOYSA-N 0.000 description 2
GNGBYGNCYWGVIW-UHFFFAOYSA-N 5-(bromomethyl)-4-methylthiophene-3-carbonitrile Chemical compound CC1=C(CBr)SC=C1C#N GNGBYGNCYWGVIW-UHFFFAOYSA-N 0.000 description 2
IRWXGDBFGWSFSF-UHFFFAOYSA-N 5-(bromomethyl)furan-2-carbonitrile Chemical compound BrCC1=CC=C(C#N)O1 IRWXGDBFGWSFSF-UHFFFAOYSA-N 0.000 description 2
HYFPPIFPJXGAJN-UHFFFAOYSA-N 5-(chloromethyl)-1,2-oxazole-3-carbonyl chloride Chemical compound ClCC1=CC(C(Cl)=O)=NO1 HYFPPIFPJXGAJN-UHFFFAOYSA-N 0.000 description 2
NWOXBDDVGBFOBB-UHFFFAOYSA-N 5-(chloromethyl)-1,2-oxazole-3-carboxamide Chemical compound NC(=O)C=1C=C(CCl)ON=1 NWOXBDDVGBFOBB-UHFFFAOYSA-N 0.000 description 2
HIRBVBHECOSUFB-UHFFFAOYSA-N 5-(hydroxyiminomethyl)thiophene-3-carbonitrile Chemical compound ON=CC1=CC(C#N)=CS1 HIRBVBHECOSUFB-UHFFFAOYSA-N 0.000 description 2
SBAVSUHIXDKUMH-UHFFFAOYSA-N 5-(hydroxymethyl)-3-methylthiophene-2-carbonitrile Chemical compound CC=1C=C(CO)SC=1C#N SBAVSUHIXDKUMH-UHFFFAOYSA-N 0.000 description 2
IGBCJVUIPUDISK-UHFFFAOYSA-N 5-(hydroxymethyl)-4-methylthiophene-3-carbonitrile Chemical compound CC1=C(CO)SC=C1C#N IGBCJVUIPUDISK-UHFFFAOYSA-N 0.000 description 2
XAOLIZQQNMUXQB-UHFFFAOYSA-N 5-(hydroxymethyl)furan-2-carbonitrile Chemical compound OCC1=CC=C(C#N)O1 XAOLIZQQNMUXQB-UHFFFAOYSA-N 0.000 description 2
NEPGMLCZUNJRSN-UHFFFAOYSA-N 5-formyl-3-methylthiophene-2-carbonitrile Chemical compound CC=1C=C(C=O)SC=1C#N NEPGMLCZUNJRSN-UHFFFAOYSA-N 0.000 description 2
PUQKOVRPNHYQIY-UHFFFAOYSA-N 5-formylfuran-2-carbonitrile Chemical compound O=CC1=CC=C(C#N)O1 PUQKOVRPNHYQIY-UHFFFAOYSA-N 0.000 description 2
DLTDLUAJPULDBI-UHFFFAOYSA-N 5-formylthiophene-3-carbonitrile Chemical compound O=CC1=CC(C#N)=CS1 DLTDLUAJPULDBI-UHFFFAOYSA-N 0.000 description 2
108010058207 Anistreplase Proteins 0.000 description 2
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
BAUAPEBNQXDJOF-UHFFFAOYSA-N CC(O)=O.CC(O)=O.NCC1=NC(C(N)=N)=CS1 Chemical compound CC(O)=O.CC(O)=O.NCC1=NC(C(N)=N)=CS1 BAUAPEBNQXDJOF-UHFFFAOYSA-N 0.000 description 2
GHIIFTIGSRUEEB-UHFFFAOYSA-N CC1=CC=C(CONC(C2=CC=C(CN)S2)=N)C=C1.Cl Chemical compound CC1=CC=C(CONC(C2=CC=C(CN)S2)=N)C=C1.Cl GHIIFTIGSRUEEB-UHFFFAOYSA-N 0.000 description 2
GFMOULUSFQOFRG-UHFFFAOYSA-N CONC(C1=CC=C(CN)S1)=N.Cl Chemical compound CONC(C1=CC=C(CN)S1)=N.Cl GFMOULUSFQOFRG-UHFFFAOYSA-N 0.000 description 2
UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
241000282472 Canis lupus familiaris Species 0.000 description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
206010051055 Deep vein thrombosis Diseases 0.000 description 2
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
238000005684 Liebig rearrangement reaction Methods 0.000 description 2
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
241001465754 Metazoa Species 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
DQBOIWVLVFBYMX-UHFFFAOYSA-N NCC1=CC(C(NO2)=NC2=O)=CS1.Cl Chemical compound NCC1=CC(C(NO2)=NC2=O)=CS1.Cl DQBOIWVLVFBYMX-UHFFFAOYSA-N 0.000 description 2
ZHRXPJZMBOVDNU-UHFFFAOYSA-N NCC1=NC(C(N)=N)=CS1.Cl.Cl Chemical compound NCC1=NC(C(N)=N)=CS1.Cl.Cl ZHRXPJZMBOVDNU-UHFFFAOYSA-N 0.000 description 2
LDJAIPNJNAOOIK-UHFFFAOYSA-N NCC1=NC(C(NO2)=NC2=O)=CS1.Cl Chemical compound NCC1=NC(C(NO2)=NC2=O)=CS1.Cl LDJAIPNJNAOOIK-UHFFFAOYSA-N 0.000 description 2
238000005481 NMR spectroscopy Methods 0.000 description 2
229910002651 NO3 Inorganic materials 0.000 description 2
NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
108010001014 Plasminogen Activators Proteins 0.000 description 2
102000001938 Plasminogen Activators Human genes 0.000 description 2
208000010378 Pulmonary Embolism Diseases 0.000 description 2
LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
206010038563 Reocclusion Diseases 0.000 description 2
108010022999 Serine Proteases Proteins 0.000 description 2
102000012479 Serine Proteases Human genes 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
108010023197 Streptokinase Proteins 0.000 description 2
101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 2
208000007536 Thrombosis Diseases 0.000 description 2
OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 2
102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 2
206010047249 Venous thrombosis Diseases 0.000 description 2
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
159000000021 acetate salts Chemical class 0.000 description 2
229960004308 acetylcysteine Drugs 0.000 description 2
235000004279 alanine Nutrition 0.000 description 2
125000005037 alkyl phenyl group Chemical group 0.000 description 2
150000001408 amides Chemical group 0.000 description 2
150000003862 amino acid derivatives Chemical class 0.000 description 2
235000003704 aspartic acid Nutrition 0.000 description 2
OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
229910052794 bromium Inorganic materials 0.000 description 2
KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 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
210000004899 c-terminal region Anatomy 0.000 description 2
239000001110 calcium chloride Substances 0.000 description 2
229910001628 calcium chloride Inorganic materials 0.000 description 2
150000001728 carbonyl compounds Chemical class 0.000 description 2
150000003857 carboxamides Chemical class 0.000 description 2
238000005119 centrifugation Methods 0.000 description 2
206010008118 cerebral infarction Diseases 0.000 description 2
208000026106 cerebrovascular disease Diseases 0.000 description 2
DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
238000007887 coronary angioplasty Methods 0.000 description 2
239000013078 crystal Substances 0.000 description 2
IWVJLGPDBXCTDA-UHFFFAOYSA-N cyclohexyl carbonochloridate Chemical compound ClC(=O)OC1CCCCC1 IWVJLGPDBXCTDA-UHFFFAOYSA-N 0.000 description 2
IIRFCWANHMSDCG-UHFFFAOYSA-N cyclooctanone Chemical compound O=C1CCCCCCC1 IIRFCWANHMSDCG-UHFFFAOYSA-N 0.000 description 2
XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 2
BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
230000018044 dehydration Effects 0.000 description 2
238000006297 dehydration reaction Methods 0.000 description 2
NMCZTUHUUFFVHP-UHFFFAOYSA-N ethyl 4-cyano-3-methylthiophene-2-carboxylate Chemical compound CCOC(=O)C=1SC=C(C#N)C=1C NMCZTUHUUFFVHP-UHFFFAOYSA-N 0.000 description 2
TUEYHEWXYWCDHA-UHFFFAOYSA-N ethyl 5-methylthiadiazole-4-carboxylate Chemical compound CCOC(=O)C=1N=NSC=1C TUEYHEWXYWCDHA-UHFFFAOYSA-N 0.000 description 2
125000004494 ethyl ester group Chemical group 0.000 description 2
WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
230000029142 excretion Effects 0.000 description 2
238000004108 freeze drying Methods 0.000 description 2
230000002496 gastric effect Effects 0.000 description 2
238000007429 general method Methods 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
125000005842 heteroatom Chemical group 0.000 description 2
KIWBRXCOTCXSSZ-UHFFFAOYSA-N hexyl carbonochloridate Chemical compound CCCCCCOC(Cl)=O KIWBRXCOTCXSSZ-UHFFFAOYSA-N 0.000 description 2
238000007327 hydrogenolysis reaction Methods 0.000 description 2
230000002401 inhibitory effect Effects 0.000 description 2
238000002347 injection Methods 0.000 description 2
239000007924 injection Substances 0.000 description 2
230000000968 intestinal effect Effects 0.000 description 2
238000002955 isolation Methods 0.000 description 2
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
239000007788 liquid Substances 0.000 description 2
229910052744 lithium Inorganic materials 0.000 description 2
BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
HQGPKMSGXAUKHT-BYPYZUCNSA-N methyl (2s)-5-oxopyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCC(=O)N1 HQGPKMSGXAUKHT-BYPYZUCNSA-N 0.000 description 2
USPRKWICHNGIJG-UHFFFAOYSA-N methyl 4-methyl-2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]-1,3-thiazole-5-carboxylate Chemical compound COC(=O)C=1SC(CNC(=O)OC(C)(C)C)=NC=1C USPRKWICHNGIJG-UHFFFAOYSA-N 0.000 description 2
CMKROYBYNNTMJP-UHFFFAOYSA-N methyl 5-methyl-2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]-1,3-thiazole-4-carboxylate Chemical compound COC(=O)C=1N=C(CNC(=O)OC(C)(C)C)SC=1C CMKROYBYNNTMJP-UHFFFAOYSA-N 0.000 description 2
MQWCXKGKQLNYQG-UHFFFAOYSA-N methyl cyclohexan-4-ol Natural products CC1CCC(O)CC1 MQWCXKGKQLNYQG-UHFFFAOYSA-N 0.000 description 2
239000012452 mother liquor Substances 0.000 description 2
230000002107 myocardial effect Effects 0.000 description 2
125000004433 nitrogen atom Chemical group N* 0.000 description 2
KPMKEVXVVHNIEY-UHFFFAOYSA-N norcamphor Chemical compound C1CC2C(=O)CC1C2 KPMKEVXVVHNIEY-UHFFFAOYSA-N 0.000 description 2
MLWXTMVARHZBPA-UHFFFAOYSA-N o-[(4-methylphenyl)methyl]hydroxylamine Chemical compound CC1=CC=C(CON)C=C1 MLWXTMVARHZBPA-UHFFFAOYSA-N 0.000 description 2
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
239000001301 oxygen Substances 0.000 description 2
229910052763 palladium Inorganic materials 0.000 description 2
230000036961 partial effect Effects 0.000 description 2
230000003285 pharmacodynamic effect Effects 0.000 description 2
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
229910052698 phosphorus Inorganic materials 0.000 description 2
229940127126 plasminogen activator Drugs 0.000 description 2
229920000642 polymer Polymers 0.000 description 2
CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 2
229910000343 potassium bisulfate Inorganic materials 0.000 description 2
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
108090000765 processed proteins & peptides Proteins 0.000 description 2
238000012545 processing Methods 0.000 description 2
229910052703 rhodium Inorganic materials 0.000 description 2
238000002390 rotary evaporation Methods 0.000 description 2
238000005070 sampling Methods 0.000 description 2
108010073863 saruplase Proteins 0.000 description 2
238000010898 silica gel chromatography Methods 0.000 description 2
239000008259 solid foam Substances 0.000 description 2
239000007921 spray Substances 0.000 description 2
229960005202 streptokinase Drugs 0.000 description 2
239000003826 tablet Substances 0.000 description 2
RBCWSAIYHCXNEW-UHFFFAOYSA-N tert-butyl n-[(4-carbamothioyl-3-methylthiophen-2-yl)methyl]-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC1=C(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)SC=C1C(N)=S RBCWSAIYHCXNEW-UHFFFAOYSA-N 0.000 description 2
LMJUNWYKTNNAOK-UHFFFAOYSA-N tert-butyl n-[(5-carbamothioyl-4-methyl-1,3-thiazol-2-yl)methyl]carbamate Chemical compound CC=1N=C(CNC(=O)OC(C)(C)C)SC=1C(N)=S LMJUNWYKTNNAOK-UHFFFAOYSA-N 0.000 description 2
OBBPAKWWPQXWCH-UHFFFAOYSA-N tert-butyl n-[(5-cyano-4-methylthiophen-2-yl)methyl]-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC=1C=C(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)SC=1C#N OBBPAKWWPQXWCH-UHFFFAOYSA-N 0.000 description 2
TWDOFAQZROCGGZ-UHFFFAOYSA-N tert-butyl n-[[5-carbamothioyl-4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=NC(C(F)(F)F)=C(C(N)=S)S1 TWDOFAQZROCGGZ-UHFFFAOYSA-N 0.000 description 2
IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 2
239000012414 tert-butyl nitrite Substances 0.000 description 2
JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
229960005356 urokinase Drugs 0.000 description 2
238000010792 warming Methods 0.000 description 2
238000010626 work up procedure Methods 0.000 description 2
FAAUGLVHTNUEGL-UHFFFAOYSA-N (1-methylcyclopentyl) 2-bromoacetate Chemical compound BrCC(=O)OC1(C)CCCC1 FAAUGLVHTNUEGL-UHFFFAOYSA-N 0.000 description 1
QSUXZIPXYDQFCX-SNVBAGLBSA-N (2r)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)C1CCCCC1 QSUXZIPXYDQFCX-SNVBAGLBSA-N 0.000 description 1
MJLQPFJGZTYCMH-LURJTMIESA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]-5-oxopyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1[C@H](C(O)=O)CCC1=O MJLQPFJGZTYCMH-LURJTMIESA-N 0.000 description 1
VQDMQFJXWAHHJA-QMMMGPOBSA-N (2s)-2-(cycloheptylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1CCCCCC1 VQDMQFJXWAHHJA-QMMMGPOBSA-N 0.000 description 1
FZTBJBZGKILHLT-FJXQXJEOSA-N (2s)-2-(cyclohexylamino)propanoic acid;hydrochloride Chemical compound Cl.OC(=O)[C@H](C)NC1CCCCC1 FZTBJBZGKILHLT-FJXQXJEOSA-N 0.000 description 1
BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 description 1
LDUWTIUXPVCEQF-LURJTMIESA-N (2s)-2-(cyclopentylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1CCCC1 LDUWTIUXPVCEQF-LURJTMIESA-N 0.000 description 1
DTGOUWNVHDROOR-LBPRGKRZSA-N (2s)-2-(dicyclohexylamino)propanoic acid Chemical compound C1CCCCC1N([C@@H](C)C(O)=O)C1CCCCC1 DTGOUWNVHDROOR-LBPRGKRZSA-N 0.000 description 1
SAUDSWFPPKSVMK-LBPRGKRZSA-N (2s)-2-(n-phenylanilino)propanoic acid Chemical compound C=1C=CC=CC=1N([C@@H](C)C(O)=O)C1=CC=CC=C1 SAUDSWFPPKSVMK-LBPRGKRZSA-N 0.000 description 1
NTUPOKHATNSWCY-PMPSAXMXSA-N (2s)-2-[[(2s)-1-[(2r)-2-amino-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=CC=C1 NTUPOKHATNSWCY-PMPSAXMXSA-N 0.000 description 1
IADUEWIQBXOCDZ-VKHMYHEASA-N (S)-azetidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCN1 IADUEWIQBXOCDZ-VKHMYHEASA-N 0.000 description 1
AAJCCSYSPIKAJY-UHFFFAOYSA-N 1,3-thiazol-2-ylmethanamine;hydrochloride Chemical compound Cl.NCC1=NC=CS1 AAJCCSYSPIKAJY-UHFFFAOYSA-N 0.000 description 1
QWEWLLNSJDTOKH-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide Chemical compound NC(=O)C1=NC=CS1 QWEWLLNSJDTOKH-UHFFFAOYSA-N 0.000 description 1
WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
ICURVXBGGDVHDT-UHFFFAOYSA-N 1-[ethoxy(isocyanomethyl)phosphoryl]oxyethane Chemical compound CCOP(=O)(C[N+]#[C-])OCC ICURVXBGGDVHDT-UHFFFAOYSA-N 0.000 description 1
RJUJXZBZYWYPGU-UHFFFAOYSA-N 1-benzhydryl-1h-indene Chemical compound C1=CC2=CC=CC=C2C1C(C=1C=CC=CC=1)C1=CC=CC=C1 RJUJXZBZYWYPGU-UHFFFAOYSA-N 0.000 description 1
RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
MMQJZQKFTWIATR-UHFFFAOYSA-N 1h-pyrazole;1h-pyrrole Chemical compound C=1C=CNC=1.C=1C=NNC=1 MMQJZQKFTWIATR-UHFFFAOYSA-N 0.000 description 1
BAYAKMPRFGNNFW-UHFFFAOYSA-N 2,4-dimethylpentan-3-ol Chemical compound CC(C)C(O)C(C)C BAYAKMPRFGNNFW-UHFFFAOYSA-N 0.000 description 1
RWVZUFKCWZTXLI-UHFFFAOYSA-N 2,4-dimethylpentan-3-yl 2-bromoacetate Chemical compound CC(C)C(C(C)C)OC(=O)CBr RWVZUFKCWZTXLI-UHFFFAOYSA-N 0.000 description 1
PCFLITIGRAACCZ-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethyl carbonochloridate Chemical compound COCCOCCOC(Cl)=O PCFLITIGRAACCZ-UHFFFAOYSA-N 0.000 description 1
GADKCBBWERTBNI-UHFFFAOYSA-N 2-(aminomethyl)-1,3-thiazole-4-carbonitrile;hydrochloride Chemical compound Cl.NCC1=NC(C#N)=CS1 GADKCBBWERTBNI-UHFFFAOYSA-N 0.000 description 1
KYXSOUQEUGTQGE-UHFFFAOYSA-N 2-(aminomethyl)-1,3-thiazole-4-carboximidamide Chemical compound NCC1=NC(C(N)=N)=CS1 KYXSOUQEUGTQGE-UHFFFAOYSA-N 0.000 description 1
RURCKNCTXDRIOD-UHFFFAOYSA-N 2-(aminomethyl)-N'-methoxy-1,3-thiazole-4-carboximidamide Chemical compound CON=C(C1=CSC(=N1)CN)N RURCKNCTXDRIOD-UHFFFAOYSA-N 0.000 description 1
XNWXKMDZICGOBZ-UHFFFAOYSA-N 2-(bromomethyl)furan-3-carbonitrile Chemical compound BrCC=1OC=CC=1C#N XNWXKMDZICGOBZ-UHFFFAOYSA-N 0.000 description 1
GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
DQLDYBXNPHLTGI-UHFFFAOYSA-N 2-(cyclooctylamino)acetic acid;hydrochloride Chemical compound Cl.OC(=O)CNC1CCCCCCC1 DQLDYBXNPHLTGI-UHFFFAOYSA-N 0.000 description 1
VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
PHQYKZFSYOBZBG-UHFFFAOYSA-N 2-[(3,3-dimethylcyclohexyl)amino]acetic acid Chemical compound CC1(C)CCCC(NCC(O)=O)C1 PHQYKZFSYOBZBG-UHFFFAOYSA-N 0.000 description 1
OZFRQBRKCGBKPX-UHFFFAOYSA-N 2-[(4-methylcyclohexyl)amino]acetic acid Chemical compound CC1CCC(NCC(O)=O)CC1 OZFRQBRKCGBKPX-UHFFFAOYSA-N 0.000 description 1
XMKPVCHWZOQKRQ-UHFFFAOYSA-N 2-[(4-methylcyclohexyl)amino]acetic acid;hydrochloride Chemical compound Cl.CC1CCC(NCC(O)=O)CC1 XMKPVCHWZOQKRQ-UHFFFAOYSA-N 0.000 description 1
NVCPODCBGRATHZ-UHFFFAOYSA-N 2-[(4-propan-2-ylcyclohexyl)amino]acetic acid Chemical compound CC(C)C1CCC(NCC(O)=O)CC1 NVCPODCBGRATHZ-UHFFFAOYSA-N 0.000 description 1
GNOLHJDXSYSJCA-UHFFFAOYSA-N 2-amino-2-(4-bicyclo[2.2.1]heptanyl)acetic acid Chemical compound C1CC2CCC1(C(C(O)=O)N)C2 GNOLHJDXSYSJCA-UHFFFAOYSA-N 0.000 description 1
ZWELPAVSPBZWNJ-UHFFFAOYSA-N 2-amino-2-(4-bicyclo[2.2.1]heptanyl)acetic acid;hydrochloride Chemical compound Cl.C1CC2CCC1(C(C(O)=O)N)C2 ZWELPAVSPBZWNJ-UHFFFAOYSA-N 0.000 description 1
XIZSUYSWKGAOCN-UHFFFAOYSA-N 2-amino-4-chloro-5-formylthiophene-3-carbonitrile Chemical compound NC=1SC(C=O)=C(Cl)C=1C#N XIZSUYSWKGAOCN-UHFFFAOYSA-N 0.000 description 1
LHNPENNQGSGOTO-UHFFFAOYSA-N 2-bromo-n,n-diethylacetamide Chemical compound CCN(CC)C(=O)CBr LHNPENNQGSGOTO-UHFFFAOYSA-N 0.000 description 1
LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical compound CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 description 1
NDYYWMXJZWHRLZ-UHFFFAOYSA-N 2-methoxyethyl carbonochloridate Chemical compound COCCOC(Cl)=O NDYYWMXJZWHRLZ-UHFFFAOYSA-N 0.000 description 1
CLSHQIDDCJTHAJ-UHFFFAOYSA-N 2-thienylacetonitrile Chemical compound N#CCC1=CC=CS1 CLSHQIDDCJTHAJ-UHFFFAOYSA-N 0.000 description 1
PCJFEVUKVKQSSL-UHFFFAOYSA-N 2h-1,2,4-oxadiazol-5-one Chemical compound O=C1N=CNO1 PCJFEVUKVKQSSL-UHFFFAOYSA-N 0.000 description 1
JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
ATWZNUYMQQXKFL-UHFFFAOYSA-N 3-(4-benzylphenyl)-3-oxopropanenitrile Chemical compound C1=CC(C(CC#N)=O)=CC=C1CC1=CC=CC=C1 ATWZNUYMQQXKFL-UHFFFAOYSA-N 0.000 description 1
FPGDDWCTBDGPAD-UHFFFAOYSA-N 3-chlorothiophene-2-carbonitrile Chemical compound ClC=1C=CSC=1C#N FPGDDWCTBDGPAD-UHFFFAOYSA-N 0.000 description 1
PUKKVMZZENXNSR-UHFFFAOYSA-N 3-chlorothiophene-2-carboxamide Chemical compound NC(=O)C=1SC=CC=1Cl PUKKVMZZENXNSR-UHFFFAOYSA-N 0.000 description 1
NLRJUIXKEMCEOH-UHFFFAOYSA-N 3-fluoropropan-1-ol Chemical compound OCCCF NLRJUIXKEMCEOH-UHFFFAOYSA-N 0.000 description 1
RBIGKSZIQCTIJF-UHFFFAOYSA-N 3-formylthiophene Chemical compound O=CC=1C=CSC=1 RBIGKSZIQCTIJF-UHFFFAOYSA-N 0.000 description 1
IFLKEBSJTZGCJG-UHFFFAOYSA-N 3-methylthiophene-2-carboxylic acid Chemical compound CC=1C=CSC=1C(O)=O IFLKEBSJTZGCJG-UHFFFAOYSA-N 0.000 description 1
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
UHDPHYPIEULDFF-UHFFFAOYSA-N 4-(aminomethyl)-1,3-thiazole-2-carbothioamide Chemical compound NCC1=CSC(C(N)=S)=N1 UHDPHYPIEULDFF-UHFFFAOYSA-N 0.000 description 1
WANJJWNJLSLRAC-UHFFFAOYSA-N 4-(aminomethyl)-1,3-thiazole-2-carbothioamide;hydrochloride Chemical compound Cl.NCC1=CSC(C(N)=S)=N1 WANJJWNJLSLRAC-UHFFFAOYSA-N 0.000 description 1
WELJMDZGAZGMIM-UHFFFAOYSA-N 4-(aminomethyl)thiophene-2-carbonitrile Chemical compound NCC1=CSC(C#N)=C1 WELJMDZGAZGMIM-UHFFFAOYSA-N 0.000 description 1
DUNNSMPSOCGFDV-UHFFFAOYSA-N 4-(aminomethyl)thiophene-2-carbonitrile;hydrochloride Chemical compound Cl.NCC1=CSC(C#N)=C1 DUNNSMPSOCGFDV-UHFFFAOYSA-N 0.000 description 1
PDONIKHDXYHTLS-UHFFFAOYSA-N 4-bromothiophene-2-carbaldehyde Chemical compound BrC1=CSC(C=O)=C1 PDONIKHDXYHTLS-UHFFFAOYSA-N 0.000 description 1
PFTGXSGDFZZZFY-UHFFFAOYSA-N 4-methoxycyclohexan-1-ol Chemical compound COC1CCC(O)CC1 PFTGXSGDFZZZFY-UHFFFAOYSA-N 0.000 description 1
KHJZJGDAXWBEKG-UHFFFAOYSA-N 4-methyl-2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]-1,3-thiazole-5-carboxylic acid Chemical compound CC=1N=C(CNC(=O)OC(C)(C)C)SC=1C(O)=O KHJZJGDAXWBEKG-UHFFFAOYSA-N 0.000 description 1
XZUAUDZGDPLDLH-UHFFFAOYSA-N 4-methylcyclohexane-1-carbaldehyde Chemical compound CC1CCC(C=O)CC1 XZUAUDZGDPLDLH-UHFFFAOYSA-N 0.000 description 1
FPKISACHVIIMRA-UHFFFAOYSA-N 4-propan-2-ylcyclohexan-1-one Chemical compound CC(C)C1CCC(=O)CC1 FPKISACHVIIMRA-UHFFFAOYSA-N 0.000 description 1
GLBRWLVEZQRTKY-UHFFFAOYSA-N 4-propan-2-ylcyclohexane-1-carbaldehyde Chemical compound CC(C)C1CCC(C=O)CC1 GLBRWLVEZQRTKY-UHFFFAOYSA-N 0.000 description 1
CCOQPGVQAWPUPE-UHFFFAOYSA-N 4-tert-butylcyclohexan-1-ol Chemical compound CC(C)(C)C1CCC(O)CC1 CCOQPGVQAWPUPE-UHFFFAOYSA-N 0.000 description 1
229940091886 4-tert-butylcyclohexanol Drugs 0.000 description 1
PYMWWSDWIWAHMF-UHFFFAOYSA-N 5-(aminomethyl)-1,2-oxazole-3-carboxamide Chemical compound NCC1=CC(C(N)=O)=NO1 PYMWWSDWIWAHMF-UHFFFAOYSA-N 0.000 description 1
GRSSUGHEBAOGRK-UHFFFAOYSA-N 5-(aminomethyl)-1,2-oxazole-3-carboxamide;hydrochloride Chemical compound Cl.NCC1=CC(C(N)=O)=NO1 GRSSUGHEBAOGRK-UHFFFAOYSA-N 0.000 description 1
YMQFFSVXGLVVTR-UHFFFAOYSA-N 5-(aminomethyl)-3,4-dimethylthiophene-2-carboxamide;hydrochloride Chemical compound Cl.CC=1C(C)=C(C(N)=O)SC=1CN YMQFFSVXGLVVTR-UHFFFAOYSA-N 0.000 description 1
ABTQIHJLNPRSFI-UHFFFAOYSA-N 5-(aminomethyl)-3-chlorothiophene-2-carbonitrile;hydrochloride Chemical compound Cl.NCC1=CC(Cl)=C(C#N)S1 ABTQIHJLNPRSFI-UHFFFAOYSA-N 0.000 description 1
PNBXOHLVMHYSNL-UHFFFAOYSA-N 5-(aminomethyl)-3-methylthiophene-2-carbonitrile;hydrochloride Chemical compound Cl.CC=1C=C(CN)SC=1C#N PNBXOHLVMHYSNL-UHFFFAOYSA-N 0.000 description 1
JCQLHILYDSQNTL-UHFFFAOYSA-N 5-(aminomethyl)-4-chlorothiophene-3-carbothioamide Chemical compound NCC=1SC=C(C(N)=S)C=1Cl JCQLHILYDSQNTL-UHFFFAOYSA-N 0.000 description 1
PZBPERMHYKZOQE-UHFFFAOYSA-N 5-(aminomethyl)-4-chlorothiophene-3-carbothioamide;hydrochloride Chemical compound Cl.NCC=1SC=C(C(N)=S)C=1Cl PZBPERMHYKZOQE-UHFFFAOYSA-N 0.000 description 1
HRAKGEWTXLDPHR-UHFFFAOYSA-N 5-(aminomethyl)-N'-methoxythiophene-2-carboximidamide Chemical compound CON=C(C1=CC=C(S1)CN)N HRAKGEWTXLDPHR-UHFFFAOYSA-N 0.000 description 1
AIBYYQLJOMFINU-UHFFFAOYSA-N 5-(aminomethyl)furan-2-carbonitrile Chemical compound NCC1=CC=C(C#N)O1 AIBYYQLJOMFINU-UHFFFAOYSA-N 0.000 description 1
VXYGVONDVBPKOY-UHFFFAOYSA-N 5-(aminomethyl)furan-2-carbonitrile;hydrochloride Chemical compound Cl.NCC1=CC=C(C#N)O1 VXYGVONDVBPKOY-UHFFFAOYSA-N 0.000 description 1
ORXSASOZUVSWPV-UHFFFAOYSA-N 5-(aminomethyl)thiophene-2-carbonitrile;hydrochloride Chemical compound Cl.NCC1=CC=C(C#N)S1 ORXSASOZUVSWPV-UHFFFAOYSA-N 0.000 description 1
IMVOSXKZSNMFDP-UHFFFAOYSA-N 5-(aminomethyl)thiophene-2-carbothioamide Chemical compound C1=C(SC(=C1)C(=S)N)CN IMVOSXKZSNMFDP-UHFFFAOYSA-N 0.000 description 1
BOBPPWFJOKHRKZ-UHFFFAOYSA-N 5-(aminomethyl)thiophene-2-carboximidamide Chemical compound NCC1=CC=C(C(N)=N)S1 BOBPPWFJOKHRKZ-UHFFFAOYSA-N 0.000 description 1
BBGRLEJFPILYFH-UHFFFAOYSA-N 5-chlorothiophene-3-carbonitrile Chemical compound ClC1=CC(C#N)=CS1 BBGRLEJFPILYFH-UHFFFAOYSA-N 0.000 description 1
OQOIWRFVVMDMOK-UHFFFAOYSA-N 5-cyano-3,4-dimethylthiophene-2-carboxamide Chemical compound CC=1C(C)=C(C(N)=O)SC=1C#N OQOIWRFVVMDMOK-UHFFFAOYSA-N 0.000 description 1
SVJXVFJTMBYODT-UHFFFAOYSA-N 5-methyl-2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]-1,3-thiazole-4-carboxylic acid Chemical compound CC=1SC(CNC(=O)OC(C)(C)C)=NC=1C(O)=O SVJXVFJTMBYODT-UHFFFAOYSA-N 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
QYPPJABKJHAVHS-UHFFFAOYSA-N Agmatine Natural products NCCCCNC(N)=N QYPPJABKJHAVHS-UHFFFAOYSA-N 0.000 description 1
229910018072 Al 2 O 3 Inorganic materials 0.000 description 1
208000024827 Alzheimer disease Diseases 0.000 description 1
206010002388 Angina unstable Diseases 0.000 description 1
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
206010003658 Atrial Fibrillation Diseases 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
102000015081 Blood Coagulation Factors Human genes 0.000 description 1
108010039209 Blood Coagulation Factors Proteins 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
FFPNGSWHRAUWAK-UHFFFAOYSA-N C(=O)(OC(C)(C)C)C1=C(N=C(S1)CN)C(=O)N.Cl.NCC=1SC=C(N1)C#N Chemical compound C(=O)(OC(C)(C)C)C1=C(N=C(S1)CN)C(=O)N.Cl.NCC=1SC=C(N1)C#N FFPNGSWHRAUWAK-UHFFFAOYSA-N 0.000 description 1
ZLTQJZSQKYYOIE-UHFFFAOYSA-N CC(C)CONC(C1=CC=C(CN)S1)=N.Cl Chemical compound CC(C)CONC(C1=CC=C(CN)S1)=N.Cl ZLTQJZSQKYYOIE-UHFFFAOYSA-N 0.000 description 1
KPFGSXBVDSGRJM-UHFFFAOYSA-N CC(O)=O.NCC1=CC=C(C(N)=N)S1 Chemical compound CC(O)=O.NCC1=CC=C(C(N)=N)S1 KPFGSXBVDSGRJM-UHFFFAOYSA-N 0.000 description 1
XZUAUDZGDPLDLH-ZKCHVHJHSA-N C[C@H]1CC[C@H](C=O)CC1 Chemical compound C[C@H]1CC[C@H](C=O)CC1 XZUAUDZGDPLDLH-ZKCHVHJHSA-N 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
101150065749 Churc1 gene Proteins 0.000 description 1
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
108010049003 Fibrinogen Proteins 0.000 description 1
102000008946 Fibrinogen Human genes 0.000 description 1
244000068988 Glycine max Species 0.000 description 1
208000032843 Hemorrhage Diseases 0.000 description 1
HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
206010061218 Inflammation Diseases 0.000 description 1
108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 1
YCQPUTODZKESPK-YFKPBYRVSA-N L-Baikiain Chemical compound OC(=O)[C@@H]1CC=CCN1 YCQPUTODZKESPK-YFKPBYRVSA-N 0.000 description 1
239000004201 L-cysteine Substances 0.000 description 1
HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 1
239000012359 Methanesulfonyl chloride Substances 0.000 description 1
GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 1
238000006845 Michael addition reaction Methods 0.000 description 1
NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 1
125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
XKDNLWFBLJBIIJ-WCCKRBBISA-N N1=CC=CC=C1.N1[C@H](C(=O)O)CCC1 Chemical compound N1=CC=CC=C1.N1[C@H](C(=O)O)CCC1 XKDNLWFBLJBIIJ-WCCKRBBISA-N 0.000 description 1
OVQYPAHJUQYIBU-UHFFFAOYSA-N NCC1=CC=C(C(NO)=N)S1.Cl Chemical compound NCC1=CC=C(C(NO)=N)S1.Cl OVQYPAHJUQYIBU-UHFFFAOYSA-N 0.000 description 1
101150104466 NOCT gene Proteins 0.000 description 1
206010028980 Neoplasm Diseases 0.000 description 1
206010033645 Pancreatitis Diseases 0.000 description 1
YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
102000012335 Plasminogen Activator Inhibitor 1 Human genes 0.000 description 1
108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 1
108010000020 Platelet Factor 3 Proteins 0.000 description 1
108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
102100038239 Protein Churchill Human genes 0.000 description 1
108010094028 Prothrombin Proteins 0.000 description 1
102100027378 Prothrombin Human genes 0.000 description 1
241000700159 Rattus Species 0.000 description 1
MNIWPZJRZMUPFB-UHFFFAOYSA-N S-amino 2-[(2-methylpropan-2-yl)oxycarbonylamino]ethanethioate Chemical compound CC(C)(C)OC(=O)NCC(=O)SN MNIWPZJRZMUPFB-UHFFFAOYSA-N 0.000 description 1
239000004133 Sodium thiosulphate Substances 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
108050006955 Tissue-type plasminogen activator Proteins 0.000 description 1
208000007814 Unstable Angina Diseases 0.000 description 1
208000024780 Urticaria Diseases 0.000 description 1
FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 description 1
125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
QVTMGLKIERGFFS-UHFFFAOYSA-N acetic acid;isocyanatoethane Chemical compound CC(O)=O.CCN=C=O QVTMGLKIERGFFS-UHFFFAOYSA-N 0.000 description 1
BEUROVCVPIQRKY-UHFFFAOYSA-N acetic acid;n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CC(O)=O.CCN(C(C)C)C(C)C BEUROVCVPIQRKY-UHFFFAOYSA-N 0.000 description 1
WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
239000012346 acetyl chloride Substances 0.000 description 1
239000003929 acidic solution Substances 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
150000001252 acrylic acid derivatives Chemical class 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
208000009956 adenocarcinoma Diseases 0.000 description 1
OQIQSTLJSLGHID-WNWIJWBNSA-N aflatoxin B1 Chemical compound C=1([C@@H]2C=CO[C@@H]2OC=1C=C(C1=2)OC)C=2OC(=O)C2=C1CCC2=O OQIQSTLJSLGHID-WNWIJWBNSA-N 0.000 description 1
QYPPJABKJHAVHS-UHFFFAOYSA-P agmatinium(2+) Chemical compound NC(=[NH2+])NCCCC[NH3+] QYPPJABKJHAVHS-UHFFFAOYSA-P 0.000 description 1
230000001476 alcoholic effect Effects 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
125000002723 alicyclic group Chemical group 0.000 description 1
230000002152 alkylating effect Effects 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
150000001412 amines Chemical class 0.000 description 1
150000003863 ammonium salts Chemical class 0.000 description 1
230000003321 amplification Effects 0.000 description 1
JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
239000003963 antioxidant agent Substances 0.000 description 1
235000006708 antioxidants Nutrition 0.000 description 1
150000001483 arginine derivatives Chemical class 0.000 description 1
125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
206010003246 arthritis Diseases 0.000 description 1
235000010323 ascorbic acid Nutrition 0.000 description 1
239000011668 ascorbic acid Substances 0.000 description 1
229960005070 ascorbic acid Drugs 0.000 description 1
208000006673 asthma Diseases 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
OVLHQUWQINALPR-UHFFFAOYSA-N azane;dichloromethane Chemical compound N.ClCCl OVLHQUWQINALPR-UHFFFAOYSA-N 0.000 description 1
PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical group NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
239000012965 benzophenone Substances 0.000 description 1
235000019445 benzyl alcohol Nutrition 0.000 description 1
HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
239000011230 binding agent Substances 0.000 description 1
230000000740 bleeding effect Effects 0.000 description 1
239000003114 blood coagulation factor Substances 0.000 description 1
238000010241 blood sampling Methods 0.000 description 1
238000009835 boiling Methods 0.000 description 1
230000031709 bromination Effects 0.000 description 1
238000005893 bromination reaction Methods 0.000 description 1
239000000872 buffer Substances 0.000 description 1
244000309464 bull Species 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
239000006227 byproduct Substances 0.000 description 1
238000004364 calculation method Methods 0.000 description 1
238000011088 calibration curve Methods 0.000 description 1
239000002775 capsule Substances 0.000 description 1
125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
150000004649 carbonic acid derivatives Chemical class 0.000 description 1
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
210000001715 carotid artery Anatomy 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
230000021164 cell adhesion Effects 0.000 description 1
229960000541 cetyl alcohol Drugs 0.000 description 1
230000008859 change Effects 0.000 description 1
239000003610 charcoal Substances 0.000 description 1
SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 1
239000003638 chemical reducing agent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
238000011097 chromatography purification Methods 0.000 description 1
238000005352 clarification Methods 0.000 description 1
238000003776 cleavage reaction Methods 0.000 description 1
238000002648 combination therapy Methods 0.000 description 1
239000012141 concentrate Substances 0.000 description 1
235000008504 concentrate Nutrition 0.000 description 1
238000010276 construction Methods 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
125000004093 cyano group Chemical group *C#N 0.000 description 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
QCRFMSUKWRQZEM-UHFFFAOYSA-N cycloheptanol Chemical compound OC1CCCCCC1 QCRFMSUKWRQZEM-UHFFFAOYSA-N 0.000 description 1
CGZZMOTZOONQIA-UHFFFAOYSA-N cycloheptanone Chemical compound O=C1CCCCCC1 CGZZMOTZOONQIA-UHFFFAOYSA-N 0.000 description 1
BMCQFFXPECPDPS-UHFFFAOYSA-N cycloheptylmethanol Chemical compound OCC1CCCCCC1 BMCQFFXPECPDPS-UHFFFAOYSA-N 0.000 description 1
SBBZAZOOOJEDAR-UHFFFAOYSA-N cycloheptylmethyl methanesulfonate Chemical compound CS(=O)(=O)OCC1CCCCCC1 SBBZAZOOOJEDAR-UHFFFAOYSA-N 0.000 description 1
GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 0.000 description 1
VSSAZBXXNIABDN-UHFFFAOYSA-N cyclohexylmethanol Chemical compound OCC1CCCCC1 VSSAZBXXNIABDN-UHFFFAOYSA-N 0.000 description 1
125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 description 1
230000009089 cytolysis Effects 0.000 description 1
238000011161 development Methods 0.000 description 1
ISOLMABRZPQKOV-UHFFFAOYSA-N diethyl 2-acetamidopropanedioate Chemical compound CCOC(=O)C(NC(C)=O)C(=O)OCC ISOLMABRZPQKOV-UHFFFAOYSA-N 0.000 description 1
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
239000002270 dispersing agent Substances 0.000 description 1
239000006185 dispersion Substances 0.000 description 1
238000004090 dissolution Methods 0.000 description 1
108010085662 ecarin Proteins 0.000 description 1
238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
230000008030 elimination Effects 0.000 description 1
238000003379 elimination reaction Methods 0.000 description 1
239000003995 emulsifying agent Substances 0.000 description 1
238000005516 engineering process Methods 0.000 description 1
230000002255 enzymatic effect Effects 0.000 description 1
229940088598 enzyme Drugs 0.000 description 1
125000004185 ester group Chemical group 0.000 description 1
AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
QUGJYNGNUBHTNS-UHFFFAOYSA-N ethyl 2-(benzhydrylideneamino)acetate Chemical compound C=1C=CC=CC=1C(=NCC(=O)OCC)C1=CC=CC=C1 QUGJYNGNUBHTNS-UHFFFAOYSA-N 0.000 description 1
OFLTVMGXJXSFJZ-UHFFFAOYSA-N ethyl 2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C=1SC(CNC(=O)OC(C)(C)C)=NC=1C(F)(F)F OFLTVMGXJXSFJZ-UHFFFAOYSA-N 0.000 description 1
YMBMCMOZIGSBOA-UHFFFAOYSA-N ethyl 2-amino-2-sulfanylideneacetate Chemical compound CCOC(=O)C(N)=S YMBMCMOZIGSBOA-UHFFFAOYSA-N 0.000 description 1
UXOLDCOJRAMLTQ-UHFFFAOYSA-N ethyl 2-chloro-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(Cl)=NO UXOLDCOJRAMLTQ-UHFFFAOYSA-N 0.000 description 1
VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
RNURPQMTRDHCNM-UHFFFAOYSA-N ethyl 5-(chloromethyl)-1,2-oxazole-3-carboxylate Chemical compound CCOC(=O)C=1C=C(CCl)ON=1 RNURPQMTRDHCNM-UHFFFAOYSA-N 0.000 description 1
NCCMCRFYSZRBBG-UHFFFAOYSA-N ethyl 5-amino-4-cyano-3-methylthiophene-2-carboxylate Chemical compound CCOC(=O)C=1SC(N)=C(C#N)C=1C NCCMCRFYSZRBBG-UHFFFAOYSA-N 0.000 description 1
229940012444 factor xiii Drugs 0.000 description 1
229940012952 fibrinogen Drugs 0.000 description 1
239000000945 filler Substances 0.000 description 1
239000007941 film coated tablet Substances 0.000 description 1
239000012467 final product Substances 0.000 description 1
125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
235000019253 formic acid Nutrition 0.000 description 1
238000009472 formulation Methods 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
ZQFYJHMUAWCEBH-UHFFFAOYSA-N furan-3-carbonitrile Chemical compound N#CC=1C=COC=1 ZQFYJHMUAWCEBH-UHFFFAOYSA-N 0.000 description 1
239000011521 glass Substances 0.000 description 1
150000002332 glycine derivatives Chemical class 0.000 description 1
239000008187 granular material Substances 0.000 description 1
238000001631 haemodialysis Methods 0.000 description 1
230000000322 hemodialysis Effects 0.000 description 1
229960002897 heparin Drugs 0.000 description 1
229920000669 heparin Polymers 0.000 description 1
125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
238000000589 high-performance liquid chromatography-mass spectrometry Methods 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
150000003840 hydrochlorides Chemical class 0.000 description 1
125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 1
230000002209 hydrophobic effect Effects 0.000 description 1
239000005457 ice water Substances 0.000 description 1
230000006872 improvement Effects 0.000 description 1
239000012535 impurity Substances 0.000 description 1
238000010874 in vitro model Methods 0.000 description 1
238000011534 incubation Methods 0.000 description 1
125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
239000011261 inert gas Substances 0.000 description 1
230000004968 inflammatory condition Effects 0.000 description 1
230000004054 inflammatory process Effects 0.000 description 1
238000003780 insertion Methods 0.000 description 1
230000037431 insertion Effects 0.000 description 1
230000003993 interaction Effects 0.000 description 1
201000004332 intermediate coronary syndrome Diseases 0.000 description 1
230000031891 intestinal absorption Effects 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
239000011630 iodine Substances 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
239000012280 lithium aluminium hydride Substances 0.000 description 1
230000014759 maintenance of location Effects 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
CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
239000000463 material Substances 0.000 description 1
239000002207 metabolite Substances 0.000 description 1
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
208000010125 myocardial infarction Diseases 0.000 description 1
MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
238000003199 nucleic acid amplification method Methods 0.000 description 1
RUMFZCKCISCDMG-UHFFFAOYSA-N o-(2-methylpropyl)hydroxylamine Chemical compound CC(C)CON RUMFZCKCISCDMG-UHFFFAOYSA-N 0.000 description 1
ZEJPMRKECMRICL-UHFFFAOYSA-N o-ethyl 2-amino-2-oxoethanethioate Chemical compound CCOC(=S)C(N)=O ZEJPMRKECMRICL-UHFFFAOYSA-N 0.000 description 1
125000002347 octyl 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])[H] 0.000 description 1
ZVTQYRVARPYRRE-UHFFFAOYSA-N oxadiazol-4-one Chemical class O=C1CON=N1 ZVTQYRVARPYRRE-UHFFFAOYSA-N 0.000 description 1
235000006408 oxalic acid Nutrition 0.000 description 1
125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
238000010647 peptide synthesis reaction Methods 0.000 description 1
239000008177 pharmaceutical agent Substances 0.000 description 1
229940124531 pharmaceutical excipient Drugs 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
108010089198 phenylalanyl-prolyl-arginine Proteins 0.000 description 1
235000011007 phosphoric acid Nutrition 0.000 description 1
125000003386 piperidinyl group Chemical group 0.000 description 1
229920000515 polycarbonate Polymers 0.000 description 1
239000004417 polycarbonate Substances 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000008569 process Effects 0.000 description 1
102000004196 processed proteins & peptides Human genes 0.000 description 1
CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 1
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
LJZPPWWHKPGCHS-UHFFFAOYSA-N propargyl chloride Chemical compound ClCC#C LJZPPWWHKPGCHS-UHFFFAOYSA-N 0.000 description 1
239000003380 propellant Substances 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
229940039716 prothrombin Drugs 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
229940107700 pyruvic acid Drugs 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
238000006722 reduction reaction Methods 0.000 description 1
238000005932 reductive alkylation reaction Methods 0.000 description 1
238000006268 reductive amination reaction Methods 0.000 description 1
230000002829 reductive effect Effects 0.000 description 1
239000013557 residual solvent Substances 0.000 description 1
230000000717 retained effect Effects 0.000 description 1
206010039083 rhinitis Diseases 0.000 description 1
210000003079 salivary gland Anatomy 0.000 description 1
230000007017 scission Effects 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
229910000029 sodium carbonate Inorganic materials 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
OTNVGWMVOULBFZ-UHFFFAOYSA-N sodium;hydrochloride Chemical compound [Na].Cl OTNVGWMVOULBFZ-UHFFFAOYSA-N 0.000 description 1
239000012265 solid product Substances 0.000 description 1
208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
238000012453 sprague-dawley rat model Methods 0.000 description 1
238000001256 steam distillation Methods 0.000 description 1
239000012258 stirred mixture Substances 0.000 description 1
229910021653 sulphate ion Inorganic materials 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
238000001356 surgical procedure Methods 0.000 description 1
238000001308 synthesis method Methods 0.000 description 1
230000002194 synthesizing effect Effects 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000007885 tablet disintegrant Substances 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
MPRVAXPGEKDTAO-UHFFFAOYSA-N tert-butyl 2-(aminomethyl)-4-carbamoyl-1,3-thiazole-5-carboxylate Chemical compound CC(C)(C)OC(=O)C=1SC(CN)=NC=1C(N)=O MPRVAXPGEKDTAO-UHFFFAOYSA-N 0.000 description 1
SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
CVAWKJKISIPBOD-UHFFFAOYSA-N tert-butyl 2-bromopropanoate Chemical compound CC(Br)C(=O)OC(C)(C)C CVAWKJKISIPBOD-UHFFFAOYSA-N 0.000 description 1
RMWVUWLBLWBQDS-UHFFFAOYSA-N tert-butyl 3-bromopropanoate Chemical compound CC(C)(C)OC(=O)CCBr RMWVUWLBLWBQDS-UHFFFAOYSA-N 0.000 description 1
AKMRWWVDUFXVMX-UHFFFAOYSA-N tert-butyl 5-(aminomethyl)-2-carbamothioyl-1,3-thiazole-4-carboxylate Chemical compound CC(C)(C)OC(=O)C=1N=C(C(N)=S)SC=1CN AKMRWWVDUFXVMX-UHFFFAOYSA-N 0.000 description 1
NILRVGXHGNPLKF-UHFFFAOYSA-N tert-butyl 5-(aminomethyl)-2-carbamoyl-1,3-thiazole-4-carboxylate Chemical compound CC(C)(C)OC(=O)C=1N=C(C(N)=O)SC=1CN NILRVGXHGNPLKF-UHFFFAOYSA-N 0.000 description 1
XWSBZYCBUOEDAI-UHFFFAOYSA-N tert-butyl 5-(aminomethyl)-2-cyano-1,3-thiazole-4-carboxylate Chemical compound CC(C)(C)OC(=O)C=1N=C(C#N)SC=1CN XWSBZYCBUOEDAI-UHFFFAOYSA-N 0.000 description 1
WLPYTPCHIRBLDT-UHFFFAOYSA-N tert-butyl n-[(3-cyano-3-methyl-2h-thiophen-2-yl)methyl]-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)CC1SC=CC1(C)C#N WLPYTPCHIRBLDT-UHFFFAOYSA-N 0.000 description 1
SJVRJSARAMRGND-UHFFFAOYSA-N tert-butyl n-[(4-carbamimidoyl-5-methyl-1,3-thiazol-2-yl)methyl]carbamate Chemical compound CC=1SC(CNC(=O)OC(C)(C)C)=NC=1C(N)=N SJVRJSARAMRGND-UHFFFAOYSA-N 0.000 description 1
VASZCOIXCLDVIE-UHFFFAOYSA-N tert-butyl n-[(5-carbamimidoyl-4-methyl-1,3-thiazol-2-yl)methyl]carbamate Chemical compound CC=1N=C(CNC(=O)OC(C)(C)C)SC=1C(N)=N VASZCOIXCLDVIE-UHFFFAOYSA-N 0.000 description 1
MIQHNPCLZRSNJD-UHFFFAOYSA-N tert-butyl n-[(5-carbamoyl-4-methyl-1,3-thiazol-2-yl)methyl]carbamate Chemical compound CC=1N=C(CNC(=O)OC(C)(C)C)SC=1C(N)=O MIQHNPCLZRSNJD-UHFFFAOYSA-N 0.000 description 1
HQCZORAKEVPXJM-UHFFFAOYSA-N tert-butyl n-[(5-cyanofuran-2-yl)methyl]-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)CC1=CC=C(C#N)O1 HQCZORAKEVPXJM-UHFFFAOYSA-N 0.000 description 1
WDRMWSUJMMRWKZ-UHFFFAOYSA-N tert-butyl n-[(5-cyanothiophen-3-yl)methyl]-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)CC1=CSC(C#N)=C1 WDRMWSUJMMRWKZ-UHFFFAOYSA-N 0.000 description 1
IATZGVWPSRPWJC-UHFFFAOYSA-N tert-butyl n-[[5-carbamimidoyl-4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=NC(C(F)(F)F)=C(C(N)=N)S1 IATZGVWPSRPWJC-UHFFFAOYSA-N 0.000 description 1
VZYXLQKRCZPLJM-UHFFFAOYSA-N tert-butyl n-[[5-carbamoyl-4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=NC(C(F)(F)F)=C(C(N)=O)S1 VZYXLQKRCZPLJM-UHFFFAOYSA-N 0.000 description 1
POCLJELMXAEOMM-UHFFFAOYSA-N tert-butyl n-[[5-cyano-4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=NC(C(F)(F)F)=C(C#N)S1 POCLJELMXAEOMM-UHFFFAOYSA-N 0.000 description 1
YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
YBRBMKDOPFTVDT-UHFFFAOYSA-O tert-butylammonium Chemical group CC(C)(C)[NH3+] YBRBMKDOPFTVDT-UHFFFAOYSA-O 0.000 description 1
150000003512 tertiary amines Chemical class 0.000 description 1
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
231100001274 therapeutic index Toxicity 0.000 description 1
QSELGEUCFNFITD-UHFFFAOYSA-N thiophene-2-carboximidamide Chemical compound NC(=N)C1=CC=CS1 QSELGEUCFNFITD-UHFFFAOYSA-N 0.000 description 1
BHAROVLESINHSM-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1.CC1=CC=CC=C1 BHAROVLESINHSM-UHFFFAOYSA-N 0.000 description 1
238000012546 transfer Methods 0.000 description 1
UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
108010036927 trypsin-like serine protease Proteins 0.000 description 1
210000003556 vascular endothelial cell Anatomy 0.000 description 1
210000003462 vein Anatomy 0.000 description 1
238000005406 washing Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
239000011701 zinc Substances 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
General Chemical & Material Sciences (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Biochemistry (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Molecular Biology (AREA)
Genetics & Genomics (AREA)
Biophysics (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Biomedical Technology (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Urology & Nephrology (AREA)
Pain & Pain Management (AREA)
Oncology (AREA)
Diabetes (AREA)
Vascular Medicine (AREA)
Hospice & Palliative Care (AREA)
Hematology (AREA)
Psychiatry (AREA)
Rheumatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Peptides Or Proteins (AREA)

BG105986A 1999-04-09 2001-10-05 Пролекарства на тромбинови инхибитори BG105986A (bg)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
DE19915930		1999-04-09
DE19934123		1999-07-23
DE19947920		1999-10-06
PCT/EP2000/003009 WO2000061609A2 (de)	1999-04-09	2000-04-05	Prodrugs von thrombininhibitoren

Publications (1)

Publication Number	Publication Date
BG105986A true BG105986A (bg)	2002-06-28

Family

ID=27219075

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BG105986A BG105986A (bg)	1999-04-09	2001-10-05	Пролекарства на тромбинови инхибитори

Country Status (18)

Country	Link
US (1)	US7144902B1 (de)
EP (1)	EP1165601A2 (de)
JP (1)	JP2002542165A (de)
KR (1)	KR20010108481A (de)
CN (1)	CN1355810A (de)
AU (1)	AU765244B2 (de)
BG (1)	BG105986A (de)
BR (1)	BR0009674A (de)
CA (1)	CA2370267A1 (de)
HK (1)	HK1046289A1 (de)
HU (1)	HUP0202401A3 (de)
IL (1)	IL145772A0 (de)
NO (1)	NO20014875L (de)
NZ (1)	NZ515026A (de)
PL (1)	PL352824A1 (de)
SK (1)	SK14222001A3 (de)
TR (1)	TR200102912T2 (de)
WO (1)	WO2000061609A2 (de)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE10064797A1 (de) *	2000-12-22	2002-06-27	Knoll Ag	Orale und parenterale pharmazeutische Formulierung, umfassend eine niedermolekulare Thrombininhibitor-Pro-Pharmakon
AU2003245060A1 (en) *	2002-06-27	2004-01-19	Lg Life Sciences Ltd.	Peptidic thrombin inhibitor compound
JP4787756B2 (ja) *	2003-05-16	2011-10-05	ナショナルバイオロジカルスタンダーズボード	活性化混合物
PT1737889E (pt)	2004-10-19	2010-12-13	Lonza Ag	Método para síntese de péptidos em fase sólida
EP3530290A1 (de) *	2005-05-05	2019-08-28	GlaxoSmithKline Intellectual Property Development Limited	Durch carboxylesterase hydrolysierbare alpha-aminosäureester-arzneikonjugate
BR122020016659B8 (pt)	2005-05-10	2021-07-27	Incyte Holdings Corp	moduladores de 2,3-dioxigenase de indolamina e métodos de modulação de atividade de inibição e de imunossupressão
TWI382974B (zh)	2005-12-20	2013-01-21	英塞特公司	作為吲哚胺２，３-二氧化酶調節劑之ｎ-羥基甲脒基雜環化物
CL2007002650A1 (es)	2006-09-19	2008-02-08	Incyte Corp	Compuestos derivados de heterociclo n-hidroxiamino; composicion farmaceutica, util para tratar cancer, infecciones virales y desordenes neurodegenerativos entre otras.
CA2663057C (en)	2006-09-19	2015-12-08	Incyte Corporation	N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
BR122019015876B8 (pt)	2008-07-08	2021-07-27	Incyte Holdings Corp	compostos derivados de 1,2,5-oxadiazóis, composição, bem como seus usos
CA2783801A1 (en) *	2009-12-18	2011-06-23	Activesite Pharmaceuticals, Inc.	Prodrugs of inhibitors of plasma kallikrein
US9206123B2 (en)	2009-12-18	2015-12-08	Activesite Pharmaceuticals, Inc.	Prodrugs of inhibitors of plasma kallikrein
EP2697196A1 (de)	2011-04-13	2014-02-19	Activesite Pharmaceuticals, Inc.	Prodrugs von plasmakallikreinhemmern
DK3066085T3 (da)	2013-11-08	2020-06-02	Incyte Holdings Corp	Fremgangsmåde til syntesen af en indolamin-2,3-dioxygenaseinhibitor
US10081624B2 (en) *	2014-08-26	2018-09-25	Takeda Pharmaceutical Company Limited	Heterocyclic compound
CN106674190B (zh) *	2016-12-13	2019-05-10	台州市创源工业技术有限公司	一种2-噻吩甲胺的合成方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IL112795A (en)	1994-03-04	2001-01-28	Astrazeneca Ab	Peptide derivatives as antithrombic agents their preparation and pharmaceutical compositions containing them
AR005245A1 (es)	1995-12-21	1999-04-28	Astrazeneca Ab	Prodrogas de inhibidores de trombina, una formulación farmaceutica que las comprende, el uso de dichas prodrogas para la manufactura de un medicamento y un procedimiento para su preparacion
IL120311A (en)	1996-03-01	2001-10-31	Akzo Nobel Nv	Serine protease inhibitors and pharmaceuticals containing them
DE19632773A1 (de) *	1996-08-14	1998-02-19	Basf Ag	Neue Thrombininhibitoren
AU2424499A (en) *	1998-01-26	1999-08-09	Basf Aktiengesellschaft	Heterocyclic amidines as callicrein protease inhibitors
WO1999037668A1 (de) *	1998-01-26	1999-07-29	Basf Aktiengesellschaft	Thrombininhibitoren
KR20000047461A (ko) *	1998-12-29	2000-07-25	성재갑	트롬빈 억제제
CZ20013577A3 (cs) *	1999-04-09	2002-07-17	Basf Aktiengesellschaft	Inhibitory komplementních proteáz s nízkou molekulovou hmotností

2000
- 2000-04-05 WO PCT/EP2000/003009 patent/WO2000061609A2/de not_active Ceased
- 2000-04-05 SK SK1422-2001A patent/SK14222001A3/sk not_active Application Discontinuation
- 2000-04-05 BR BR0009674-1A patent/BR0009674A/pt not_active IP Right Cessation
- 2000-04-05 CN CN00807958A patent/CN1355810A/zh active Pending
- 2000-04-05 HU HU0202401A patent/HUP0202401A3/hu unknown
- 2000-04-05 AU AU41156/00A patent/AU765244B2/en not_active Ceased
- 2000-04-05 JP JP2000611551A patent/JP2002542165A/ja active Pending
- 2000-04-05 HK HK02107849.6A patent/HK1046289A1/zh unknown
- 2000-04-05 EP EP00920661A patent/EP1165601A2/de not_active Withdrawn
- 2000-04-05 IL IL14577200A patent/IL145772A0/xx unknown
- 2000-04-05 CA CA002370267A patent/CA2370267A1/en not_active Abandoned
- 2000-04-05 US US09/958,349 patent/US7144902B1/en not_active Expired - Fee Related
- 2000-04-05 TR TR2001/02912T patent/TR200102912T2/xx unknown
- 2000-04-05 NZ NZ515026A patent/NZ515026A/en unknown
- 2000-04-05 PL PL00352824A patent/PL352824A1/xx unknown
- 2000-04-05 KR KR1020017012870A patent/KR20010108481A/ko not_active Ceased
2001
- 2001-10-05 BG BG105986A patent/BG105986A/bg unknown
- 2001-10-08 NO NO20014875A patent/NO20014875L/no not_active Application Discontinuation

Also Published As

Publication number	Publication date
IL145772A0 (en)	2002-07-25
PL352824A1 (en)	2003-09-08
NO20014875L (no)	2001-11-13
JP2002542165A (ja)	2002-12-10
CA2370267A1 (en)	2000-10-19
EP1165601A2 (de)	2002-01-02
CN1355810A (zh)	2002-06-26
KR20010108481A (ko)	2001-12-07
NO20014875D0 (no)	2001-10-08
BR0009674A (pt)	2002-01-15
TR200102912T2 (tr)	2002-03-21
SK14222001A3 (sk)	2002-07-02
US7144902B1 (en)	2006-12-05
HUP0202401A3 (en)	2003-11-28
AU4115600A (en)	2000-11-14
NZ515026A (en)	2003-10-31
WO2000061609A2 (de)	2000-10-19
HUP0202401A2 (en)	2002-10-28
WO2000061609A3 (de)	2001-03-15
WO2000061609B1 (de)	2001-04-26
HK1046289A1 (zh)	2003-01-03
AU765244B2 (en)	2003-09-11

Publication	Publication Date	Title
AU772024B2 (en)	2004-04-08	Inhibitors of urokinase and blood vessel formation
EP1808440B1 (de)	2011-07-27	Nicht-kovalente Inhibitoren von Urokinase und Blutgefäßbildung
BG105986A (bg)	2002-06-28	Пролекарства на тромбинови инхибитори
US6114358A (en)	2000-09-05	Thrombin inhibitors
CA2193844A1 (en)	1996-02-08	Thrombin inhibitors
US6740647B1 (en)	2004-05-25	Thrombin inhibitors
WO1999037611A1 (de)	1999-07-29	Heterocyclische amidine als kallikrein protease inhibitoren
AU3659200A (en)	2000-11-14	Prodrugs of thrombin inhibitors
MXPA01010119A (en)	2002-06-05	Prodrugs of thrombin inhibitors
MXPA01010118A (en)	2002-06-05	Prodrugs of thrombin inhibitors
CZ20002463A3 (cs)	2000-10-11	Nové inhibitory trombinu
CZ2001276A3 (cs)	2001-06-13	Inhibitory urokinázy a farmaceutický prostředek, který je obsahuje