EA015942B1 - Замещенные имидазолы, композиция на их основе, способ профилактики или лечения нежелательного тромбообразования с их помощью и способ ингибирования коагуляции образцов крови - Google Patents

Info

Publication number

EA015942B1

EA015942B1 EA200802288A EA200802288A EA015942B1 EA 015942 B1 EA015942 B1 EA 015942B1 EA 200802288 A EA200802288 A EA 200802288A EA 200802288 A EA200802288 A EA 200802288A EA 015942 B1 EA015942 B1 EA 015942B1

Authority

EA

Eurasian Patent Office

Prior art keywords

mmol

group

alkyl

methyl

mixture

Prior art date

2006-05-05

Links

• Espacenet
• Global Dossier
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• 239000000203 mixture Chemical class 0.000 title claims abstract description 260
• 238000000034 method Methods 0.000 title claims abstract description 39
• 150000002460 imidazoles Chemical class 0.000 title claims abstract description 34
• 208000007536 Thrombosis Diseases 0.000 title claims abstract description 21
• 210000004369 blood Anatomy 0.000 title claims abstract description 9
• 239000008280 blood Substances 0.000 title claims abstract description 9
• 230000002401 inhibitory effect Effects 0.000 title claims abstract description 7
• 230000015271 coagulation Effects 0.000 title claims abstract description 6
• 238000005345 coagulation Methods 0.000 title claims abstract description 6
• 150000003839 salts Chemical class 0.000 claims abstract description 55
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 38
• 201000010099 disease Diseases 0.000 claims abstract description 31
• 150000002148 esters Chemical class 0.000 claims abstract description 31
• -1 hydroxy, amino Chemical group 0.000 claims description 250
• 150000001875 compounds Chemical class 0.000 claims description 175
• 125000000217 alkyl group Chemical group 0.000 claims description 86
• 239000001257 hydrogen Substances 0.000 claims description 70
• 229910052739 hydrogen Inorganic materials 0.000 claims description 70
• 229910052736 halogen Inorganic materials 0.000 claims description 50
• 150000002367 halogens Chemical class 0.000 claims description 50
• 125000001424 substituent group Chemical group 0.000 claims description 41
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
• 125000001072 heteroaryl group Chemical group 0.000 claims description 35
• 150000002431 hydrogen Chemical class 0.000 claims description 33
• 125000003545 alkoxy group Chemical group 0.000 claims description 28
• 125000003118 aryl group Chemical group 0.000 claims description 27
• 125000000623 heterocyclic group Chemical group 0.000 claims description 26
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
• 125000004432 carbon atom Chemical group C* 0.000 claims description 18
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
• 125000004043 oxo group Chemical group O=* 0.000 claims description 17
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
• 125000004122 cyclic group Chemical group 0.000 claims description 16
• 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 claims description 15
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
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• 238000011282 treatment Methods 0.000 claims description 11
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
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• 239000000126 substance Substances 0.000 claims description 7
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
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• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 125000004434 sulfur atom Chemical group 0.000 claims description 6
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
• 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 claims description 5
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
• 229920006395 saturated elastomer Polymers 0.000 claims description 5
• 239000011593 sulfur Substances 0.000 claims description 5
• 208000011580 syndromic disease Diseases 0.000 claims description 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
• 206010043647 Thrombotic Stroke Diseases 0.000 claims description 4
• 206010047249 Venous thrombosis Diseases 0.000 claims description 4
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
• 150000001721 carbon Chemical group 0.000 claims description 4
• 230000000747 cardiac effect Effects 0.000 claims description 4
• 239000011737 fluorine Substances 0.000 claims description 4
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• 229910052760 oxygen Chemical group 0.000 claims description 4
• 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 3
• 206010002383 Angina Pectoris Diseases 0.000 claims description 3
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• 206010053567 Coagulopathies Diseases 0.000 claims description 3
• 206010011091 Coronary artery thrombosis Diseases 0.000 claims description 3
• 206010051055 Deep vein thrombosis Diseases 0.000 claims description 3
• 208000010378 Pulmonary Embolism Diseases 0.000 claims description 3
• 208000007814 Unstable Angina Diseases 0.000 claims description 3
• 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 3
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• 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 3
• 229910052740 iodine Inorganic materials 0.000 claims description 3
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• 238000002560 therapeutic procedure Methods 0.000 claims description 3
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• 208000033386 Buerger disease Diseases 0.000 claims description 2
• 206010043540 Thromboangiitis obliterans Diseases 0.000 claims description 2
• 230000004087 circulation Effects 0.000 claims description 2
• 125000001188 haloalkyl group Chemical group 0.000 claims description 2
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
• 208000005189 Embolism Diseases 0.000 claims 1
• 208000006011 Stroke Diseases 0.000 claims 1
• 208000032109 Transient ischaemic attack Diseases 0.000 claims 1
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• 108010074860 Factor Xa Proteins 0.000 abstract description 51
• 239000003112 inhibitor Substances 0.000 abstract description 10
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 118
• 239000000243 solution Substances 0.000 description 87
• 238000004128 high performance liquid chromatography Methods 0.000 description 73
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 65
• 239000000460 chlorine Substances 0.000 description 64
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 58
• 229910052801 chlorine Inorganic materials 0.000 description 58
• 239000005725 8-Hydroxyquinoline Substances 0.000 description 46
• 229960003540 oxyquinoline Drugs 0.000 description 46
• MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 46
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
• 238000003756 stirring Methods 0.000 description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 35
• 239000007787 solid Substances 0.000 description 32
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
• 239000000725 suspension Substances 0.000 description 24
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 22
• 229940125773 compound 10 Drugs 0.000 description 19
• ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 19
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• 241000700159 Rattus Species 0.000 description 14
• 238000006243 chemical reaction Methods 0.000 description 14
• 238000001990 intravenous administration Methods 0.000 description 14
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• 239000000706 filtrate Substances 0.000 description 13
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• 239000011777 magnesium Substances 0.000 description 12
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• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 239000000741 silica gel Substances 0.000 description 12
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