SK284915B6 - Trombínové inhibítory a ich použitie - Google Patents

Info

Publication number

SK284915B6

SK284915B6 SK8-99A SK899A SK284915B6 SK 284915 B6 SK284915 B6 SK 284915B6 SK 899 A SK899 A SK 899A SK 284915 B6 SK284915 B6 SK 284915B6

Authority

SK

Slovakia

Prior art keywords

mmol

alkyl

sic

hooc

solution

Prior art date

1996-08-14

Links

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• Global Dossier
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• 229940122388 Thrombin inhibitor Drugs 0.000 title description 5
• 239000003868 thrombin inhibitor Substances 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 41
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
• 201000010099 disease Diseases 0.000 claims abstract description 16
• 150000003839 salts Chemical class 0.000 claims abstract description 11
• 239000002253 acid Substances 0.000 claims abstract description 8
• 150000007513 acids Chemical class 0.000 claims abstract description 5
• 239000003814 drug Substances 0.000 claims abstract description 4
• 229910052739 hydrogen Inorganic materials 0.000 claims description 39
• 108090000190 Thrombin Proteins 0.000 claims description 32
• 229910052799 carbon Inorganic materials 0.000 claims description 32
• 229960004072 thrombin Drugs 0.000 claims description 31
• 102000001399 Kallikrein Human genes 0.000 claims description 16
• 108060005987 Kallikrein Proteins 0.000 claims description 16
• 229910052760 oxygen Inorganic materials 0.000 claims description 13
• 230000001419 dependent effect Effects 0.000 claims description 12
• 125000000217 alkyl group Chemical group 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 229910052717 sulfur Inorganic materials 0.000 claims description 9
• 206010038563 Reocclusion Diseases 0.000 claims description 6
• 230000008756 pathogenetic mechanism Effects 0.000 claims description 6
• 230000005764 inhibitory process Effects 0.000 claims description 5
• 208000006673 asthma Diseases 0.000 claims description 4
• 230000002797 proteolythic effect Effects 0.000 claims description 4
• 210000000329 smooth muscle myocyte Anatomy 0.000 claims description 4
• 208000005189 Embolism Diseases 0.000 claims description 3
• 206010027476 Metastases Diseases 0.000 claims description 3
• 238000009825 accumulation Methods 0.000 claims description 3
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• 230000021164 cell adhesion Effects 0.000 claims description 3
• 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 3
• 208000027866 inflammatory disease Diseases 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 230000009401 metastasis Effects 0.000 claims description 3
• 230000010410 reperfusion Effects 0.000 claims description 3
• 208000037803 restenosis Diseases 0.000 claims description 3
• 206010039083 rhinitis 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
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
• 239000005977 Ethylene Substances 0.000 claims description 2
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• 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
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• KKJUPNGICOCCDW-UHFFFAOYSA-N 7-N,N-Dimethylamino-1,2,3,4,5-pentathiocyclooctane Chemical compound CN(C)C1CSSSSSC1 KKJUPNGICOCCDW-UHFFFAOYSA-N 0.000 claims 1
• 230000014509 gene expression Effects 0.000 claims 1
• 238000004381 surface treatment Methods 0.000 claims 1
• 238000002360 preparation method Methods 0.000 abstract description 10
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 278
• 239000000243 solution Substances 0.000 description 124
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
• -1 heterocyclic amidines Chemical class 0.000 description 102
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 81
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
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• 239000000203 mixture Substances 0.000 description 60
• 239000002904 solvent Substances 0.000 description 60
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
• 239000000047 product Substances 0.000 description 54
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 48
• 238000003756 stirring Methods 0.000 description 44
• 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 37
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
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• 239000012043 crude product Substances 0.000 description 33
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
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• 238000006243 chemical reaction Methods 0.000 description 32
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• 235000011152 sodium sulphate Nutrition 0.000 description 31
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• 230000002829 reductive effect Effects 0.000 description 29
• 239000012074 organic phase Substances 0.000 description 27
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
• 239000011541 reaction mixture Substances 0.000 description 20
• 125000006239 protecting group Chemical group 0.000 description 19
• 230000015572 biosynthetic process Effects 0.000 description 18
• 238000001816 cooling Methods 0.000 description 18
• 238000000034 method Methods 0.000 description 17
• 238000003786 synthesis reaction Methods 0.000 description 17
• 238000005160 1H NMR spectroscopy Methods 0.000 description 16
• 229960004106 citric acid Drugs 0.000 description 16
• 235000015165 citric acid Nutrition 0.000 description 16
• 239000000741 silica gel Substances 0.000 description 16
• 229910002027 silica gel Inorganic materials 0.000 description 16
• 125000004093 cyano group Chemical group *C#N 0.000 description 15
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
• 239000003921 oil Substances 0.000 description 14
• 239000012071 phase Substances 0.000 description 14
• 239000000725 suspension Substances 0.000 description 13
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 239000008346 aqueous phase Substances 0.000 description 12
• 238000001035 drying Methods 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
• 229960000583 acetic acid Drugs 0.000 description 11
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
• 238000004587 chromatography analysis Methods 0.000 description 10
• 238000004440 column chromatography Methods 0.000 description 10
• 239000000543 intermediate Substances 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 238000000746 purification Methods 0.000 description 10
• 239000007787 solid Substances 0.000 description 10
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 9
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• 235000001014 amino acid Nutrition 0.000 description 9
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• 239000000706 filtrate Substances 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
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• 238000005859 coupling reaction Methods 0.000 description 8
• PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical class NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 8
• 239000001257 hydrogen Substances 0.000 description 8
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
• 239000003208 petroleum Substances 0.000 description 8
• 238000012360 testing method Methods 0.000 description 8
• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
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• 150000008064 anhydrides Chemical class 0.000 description 7
• 239000000872 buffer Substances 0.000 description 7
• 230000008878 coupling Effects 0.000 description 7
• 238000010168 coupling process Methods 0.000 description 7
• 238000003818 flash chromatography Methods 0.000 description 7
• 239000003112 inhibitor Substances 0.000 description 7
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
• 235000019341 magnesium sulphate Nutrition 0.000 description 7
• 229910052757 nitrogen Inorganic materials 0.000 description 7
• 239000000843 powder Substances 0.000 description 7
• 239000002244 precipitate Substances 0.000 description 7
• MDVRXWAAVDTLFJ-UHFFFAOYSA-N 5-methylfuran-3-carboxylic acid Chemical compound CC1=CC(C(O)=O)=CO1 MDVRXWAAVDTLFJ-UHFFFAOYSA-N 0.000 description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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• ORXSASOZUVSWPV-UHFFFAOYSA-N 5-(aminomethyl)thiophene-2-carbonitrile;hydrochloride Chemical compound Cl.NCC1=CC=C(C#N)S1 ORXSASOZUVSWPV-UHFFFAOYSA-N 0.000 description 5
• 125000006414 CCl Chemical group ClC* 0.000 description 5
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• 150000001413 amino acids Chemical class 0.000 description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
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• WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
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• 238000002835 absorbance Methods 0.000 description 4
• AIRDEHUVHXZPGV-UHFFFAOYSA-N acetic acid tert-butyl N-[(5-carbamimidoyl-1-methylpyrrol-2-yl)methyl]carbamate Chemical compound CC(O)=O.CN1C(CNC(=O)OC(C)(C)C)=CC=C1C(N)=N AIRDEHUVHXZPGV-UHFFFAOYSA-N 0.000 description 4
• 229960004308 acetylcysteine Drugs 0.000 description 4
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
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• KWADKXWQVLDXEI-UHFFFAOYSA-N ethyl 2-formamidoprop-2-enoate Chemical class CCOC(=O)C(=C)NC=O KWADKXWQVLDXEI-UHFFFAOYSA-N 0.000 description 4
• GJHRNVHKYORPQP-UHFFFAOYSA-N ethyl 2-formyl-4-oxopentanoate Chemical compound CCOC(=O)C(C=O)CC(C)=O GJHRNVHKYORPQP-UHFFFAOYSA-N 0.000 description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
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