CA2455989A1 - Neuroprotective treatment methods using selective inos inhibitors - Google Patents

Info

Publication number

CA2455989A1

CA2455989A1 CA002455989A CA2455989A CA2455989A1 CA 2455989 A1 CA2455989 A1 CA 2455989A1 CA 002455989 A CA002455989 A CA 002455989A CA 2455989 A CA2455989 A CA 2455989A CA 2455989 A1 CA2455989 A1 CA 2455989A1

Authority

CA

Canada

Prior art keywords

alkyl

halo

alkoxy

group

product

Prior art date

2001-09-24

Legal status (The legal status 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 status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
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• 238000000034 method Methods 0.000 title claims abstract description 85
• 238000011282 treatment Methods 0.000 title claims abstract description 22
• 230000000324 neuroprotective effect Effects 0.000 title claims abstract description 13
• 239000003112 inhibitor Substances 0.000 title description 26
• 101100396994 Drosophila melanogaster Inos gene Proteins 0.000 title 1
• 230000000626 neurodegenerative effect Effects 0.000 claims abstract description 24
• 229940124639 Selective inhibitor Drugs 0.000 claims abstract description 16
• 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 claims abstract description 13
• 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 claims abstract description 11
• 230000002265 prevention Effects 0.000 claims abstract description 6
• -1 heteroaralkoxy Chemical group 0.000 claims description 143
• 150000001875 compounds Chemical class 0.000 claims description 117
• 125000005843 halogen group Chemical group 0.000 claims description 114
• 125000000217 alkyl group Chemical group 0.000 claims description 109
• 125000003545 alkoxy group Chemical group 0.000 claims description 99
• 150000003839 salts Chemical class 0.000 claims description 57
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 47
• 229910052739 hydrogen Inorganic materials 0.000 claims description 46
• 125000000623 heterocyclic group Chemical group 0.000 claims description 35
• 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 28
• 239000001257 hydrogen Substances 0.000 claims description 28
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
• 229910052757 nitrogen Inorganic materials 0.000 claims description 27
• 229910052736 halogen Inorganic materials 0.000 claims description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
• 125000003118 aryl group Chemical group 0.000 claims description 21
• 150000002367 halogens Chemical class 0.000 claims description 20
• 125000001072 heteroaryl group Chemical group 0.000 claims description 20
• 125000001424 substituent group Chemical group 0.000 claims description 20
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
• 125000004429 atom Chemical group 0.000 claims description 17
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• 125000000304 alkynyl group Chemical group 0.000 claims description 14
• 206010008118 cerebral infarction Diseases 0.000 claims description 13
• 201000006474 Brain Ischemia Diseases 0.000 claims description 12
• 206010008120 Cerebral ischaemia Diseases 0.000 claims description 12
• 125000003342 alkenyl group Chemical group 0.000 claims description 12
• 208000006011 Stroke Diseases 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 208000024827 Alzheimer disease Diseases 0.000 claims description 8
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
• 125000004414 alkyl thio group Chemical group 0.000 claims description 8
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• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
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• 239000000651 prodrug Substances 0.000 claims description 5
• 229940002612 prodrug Drugs 0.000 claims description 5
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
• 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 4
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
• 125000005354 acylalkyl group Chemical group 0.000 claims description 3
• 125000004442 acylamino group Chemical group 0.000 claims description 3
• 125000004423 acyloxy group Chemical group 0.000 claims description 3
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• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 3
• 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 3
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 3
• 125000005466 alkylenyl group Chemical group 0.000 claims description 3
• 125000005018 aryl alkenyl group Chemical group 0.000 claims description 3
• 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 3
• 125000001769 aryl amino group Chemical group 0.000 claims description 3
• 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 3
• 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 3
• 125000005421 aryl sulfonamido group Chemical group 0.000 claims description 3
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
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• 125000004104 aryloxy group Chemical group 0.000 claims description 3
• 125000001589 carboacyl group Chemical group 0.000 claims description 3
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 3
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• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
• 125000004967 formylalkyl group Chemical group 0.000 claims description 3
• 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 3
• 125000001188 haloalkyl group Chemical group 0.000 claims description 3
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• 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 3
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
• 125000005241 heteroarylamino group Chemical group 0.000 claims description 3
• 125000005326 heteroaryloxy alkyl group Chemical group 0.000 claims description 3
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 3
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• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 3
• 125000005368 heteroarylthio group Chemical group 0.000 claims description 3
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
• 239000011593 sulfur Substances 0.000 claims description 3
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• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
• 125000003435 aroyl group Chemical group 0.000 claims description 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
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• 238000002560 therapeutic procedure Methods 0.000 abstract description 6
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• 239000000203 mixture Substances 0.000 description 162
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• 235000019439 ethyl acetate Nutrition 0.000 description 146
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• 238000005160 1H NMR spectroscopy Methods 0.000 description 139
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• 238000006243 chemical reaction Methods 0.000 description 106
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 105
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 104
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 104
• 101150041968 CDC13 gene Proteins 0.000 description 103
• 239000011541 reaction mixture Substances 0.000 description 101
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 99
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 97
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 92
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• 239000012044 organic layer Substances 0.000 description 70
• 239000002904 solvent Substances 0.000 description 62
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• 239000010410 layer Substances 0.000 description 55
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 55
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• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
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• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 27
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