TW201132632A - Carboxamide compounds and their use as calpain inhibitors IV - Google Patents

Info

Publication number

TW201132632A

TW201132632A TW099145352A TW99145352A TW201132632A TW 201132632 A TW201132632 A TW 201132632A TW 099145352 A TW099145352 A TW 099145352A TW 99145352 A TW99145352 A TW 99145352A TW 201132632 A TW201132632 A TW 201132632A

Authority

TW

Taiwan

Prior art keywords

phenyl

alkyl

group

propyl

aryl

Prior art date

2009-12-22

Links

• Espacenet
• Global Dossier
• Discuss

• -1 Carboxamide compounds Chemical class 0.000 title claims abstract description 1535
• 108010079785 calpain inhibitors Proteins 0.000 title description 20
• 150000001875 compounds Chemical class 0.000 claims abstract description 248
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 79
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 24
• 150000003839 salts Chemical class 0.000 claims abstract description 24
• 230000000694 effects Effects 0.000 claims abstract description 23
• 150000002367 halogens Chemical class 0.000 claims abstract description 19
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 15
• 150000004677 hydrates Chemical class 0.000 claims abstract description 12
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract 2
• 125000000217 alkyl group Chemical group 0.000 claims description 215
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 165
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 114
• 125000003118 aryl group Chemical group 0.000 claims description 73
• 150000001408 amides Chemical class 0.000 claims description 72
• 239000007789 gas Substances 0.000 claims description 68
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 66
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 62
• 125000001424 substituent group Chemical group 0.000 claims description 62
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 53
• 125000003545 alkoxy group Chemical group 0.000 claims description 50
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 49
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 49
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 48
• 150000001412 amines Chemical class 0.000 claims description 47
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 45
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 30
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 30
• 238000000034 method Methods 0.000 claims description 28
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 26
• 230000006378 damage Effects 0.000 claims description 26
• VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 claims description 25
• 125000004432 carbon atom Chemical group C* 0.000 claims description 25
• 229910052757 nitrogen Inorganic materials 0.000 claims description 24
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 23
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 22
• MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 claims description 21
• 229910052731 fluorine Inorganic materials 0.000 claims description 21
• 239000011570 nicotinamide Substances 0.000 claims description 21
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• 229910052799 carbon Inorganic materials 0.000 claims description 20
• 239000000651 prodrug Substances 0.000 claims description 20
• 229940002612 prodrug Drugs 0.000 claims description 20
• 229910052717 sulfur Inorganic materials 0.000 claims description 20
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
• ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 18
• 125000000623 heterocyclic group Chemical group 0.000 claims description 18
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
• 238000012360 testing method Methods 0.000 claims description 18
• 125000003342 alkenyl group Chemical group 0.000 claims description 17
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• 125000005842 heteroatom Chemical group 0.000 claims description 17
• 108091005804 Peptidases Proteins 0.000 claims description 16
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 14
• 125000004429 atom Chemical group 0.000 claims description 13
• 125000001188 haloalkyl group Chemical group 0.000 claims description 13
• KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 12
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• 239000011664 nicotinic acid Substances 0.000 claims description 12
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 11
• 125000000304 alkynyl group Chemical group 0.000 claims description 11
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
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• 238000013100 final test Methods 0.000 claims description 11
• 125000005843 halogen group Chemical group 0.000 claims description 11
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 10
• DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 10
• 229960002715 nicotine Drugs 0.000 claims description 10
• SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 10
• 230000036407 pain Effects 0.000 claims description 10
• 229910052707 ruthenium Inorganic materials 0.000 claims description 10
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 10
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
• MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 9
• 150000002923 oximes Chemical class 0.000 claims description 9
• SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 8
• 125000004414 alkyl thio group Chemical group 0.000 claims description 8
• 239000004202 carbamide Substances 0.000 claims description 8
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
• 239000001301 oxygen Substances 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
• 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 7
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
• 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 claims description 7
• 208000024827 Alzheimer disease Diseases 0.000 claims description 6
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 6
• 201000004792 malaria Diseases 0.000 claims description 6
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 6
• 150000003254 radicals Chemical class 0.000 claims description 6
• 239000000126 substance Substances 0.000 claims description 6
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 5
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
• 210000004556 brain Anatomy 0.000 claims description 5
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• 229960000485 methotrexate Drugs 0.000 claims description 5
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• 229910052708 sodium Inorganic materials 0.000 claims description 5
• 239000011734 sodium Substances 0.000 claims description 5
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 5
• 208000002177 Cataract Diseases 0.000 claims description 4
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
• FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 4
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• 230000003683 cardiac damage Effects 0.000 claims description 4
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
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• 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 3
• LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 claims description 3
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