PT2739628T - Novos macrociclos como inibidores de fator xia - Google Patents

Info

Publication number

PT2739628T

PT2739628T PT127624278T PT12762427T PT2739628T PT 2739628 T PT2739628 T PT 2739628T PT 127624278 T PT127624278 T PT 127624278T PT 12762427 T PT12762427 T PT 12762427T PT 2739628 T PT2739628 T PT 2739628T

Authority

PT

Portugal

Prior art keywords

alkyl

mmol

added

compounds

pharmaceutically acceptable

Prior art date

2011-08-05

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• 239000003112 inhibitor Substances 0.000 title description 53
• 150000002678 macrocyclic compounds Chemical class 0.000 title description 20
• 150000001875 compounds Chemical class 0.000 claims description 206
• -1 CH20H Chemical compound 0.000 claims description 95
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 69
• 238000000034 method Methods 0.000 claims description 69
• 150000003839 salts Chemical class 0.000 claims description 62
• 125000000217 alkyl group Chemical group 0.000 claims description 58
• 208000035475 disorder Diseases 0.000 claims description 56
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• 208000007536 Thrombosis Diseases 0.000 claims description 50
• 125000000623 heterocyclic group Chemical group 0.000 claims description 49
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 44
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 44
• 229910052799 carbon Inorganic materials 0.000 claims description 42
• 229910052739 hydrogen Inorganic materials 0.000 claims description 39
• 239000012453 solvate Substances 0.000 claims description 39
• 238000011282 treatment Methods 0.000 claims description 33
• 229910052757 nitrogen Inorganic materials 0.000 claims description 30
• 125000004432 carbon atom Chemical group C* 0.000 claims description 28
• 229910052736 halogen Inorganic materials 0.000 claims description 26
• 150000002367 halogens Chemical class 0.000 claims description 26
• 229910052760 oxygen Inorganic materials 0.000 claims description 23
• 239000008194 pharmaceutical composition Substances 0.000 claims description 23
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 21
• 229910052717 sulfur Inorganic materials 0.000 claims description 20
• 206010047249 Venous thrombosis Diseases 0.000 claims description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
• 125000003118 aryl group Chemical group 0.000 claims description 17
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• 125000005842 heteroatom Chemical group 0.000 claims description 17
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• 125000004429 atom Chemical group 0.000 claims description 14
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• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
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• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
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• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
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• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
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• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
• 208000010378 Pulmonary Embolism Diseases 0.000 claims description 8
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 8
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
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• 125000002947 alkylene group Chemical group 0.000 claims description 7
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• 206010008088 Cerebral artery embolism Diseases 0.000 claims description 6
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• 125000004450 alkenylene group Chemical group 0.000 claims description 6
• 230000002526 effect on cardiovascular system Effects 0.000 claims description 6
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• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 6
• 201000010875 transient cerebral ischemia Diseases 0.000 claims description 6
• 206010011091 Coronary artery thrombosis Diseases 0.000 claims description 5
• 206010014513 Embolism arterial Diseases 0.000 claims description 5
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• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
• 200000000007 Arterial disease Diseases 0.000 claims description 3
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
• LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical group O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 2
• 230000003836 peripheral circulation Effects 0.000 claims description 2
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• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
• 229910052698 phosphorus Inorganic materials 0.000 claims 1
• 239000000543 intermediate Substances 0.000 description 319
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• 239000000203 mixture Substances 0.000 description 80
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• 235000002639 sodium chloride Nutrition 0.000 description 62
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
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• 229910000041 hydrogen chloride Inorganic materials 0.000 description 48
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 42
• 239000002904 solvent Substances 0.000 description 42
• 239000012267 brine Substances 0.000 description 41
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 41
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
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• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 31
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
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• PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 28
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• 230000004913 activation Effects 0.000 description 23
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
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