DK3107900T3 - 5-BENZYLISOQUINOLINE DERIVATIVES FOR TREATING CARDIOVASCULAR DISEASES - Google Patents

Info

Publication number

DK3107900T3

DK3107900T3 DK15709289.1T DK15709289T DK3107900T3 DK 3107900 T3 DK3107900 T3 DK 3107900T3 DK 15709289 T DK15709289 T DK 15709289T DK 3107900 T3 DK3107900 T3 DK 3107900T3

Authority

DK

Denmark

Prior art keywords

nmr

dmso

group

protocol

pharmaceutically acceptable

Prior art date

2014-02-21

Links

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• 208000024172 Cardiovascular disease Diseases 0.000 title description 2
• 150000005520 5-benzylisoquinolines Chemical class 0.000 title 1
• 230000015572 biosynthetic process Effects 0.000 claims abstract description 34
• 238000011282 treatment Methods 0.000 claims abstract description 34
• 238000003786 synthesis reaction Methods 0.000 claims abstract description 29
• 230000004913 activation Effects 0.000 claims abstract description 9
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• 230000026731 phosphorylation Effects 0.000 claims abstract description 7
• 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 7
• 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 claims abstract description 6
• 101150111584 RHOA gene Proteins 0.000 claims abstract description 6
• 230000007170 pathology Effects 0.000 claims abstract description 6
• 230000002265 prevention Effects 0.000 claims abstract description 5
• 230000037361 pathway Effects 0.000 claims abstract description 4
• 238000005859 coupling reaction Methods 0.000 claims description 114
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 113
• 150000001875 compounds Chemical class 0.000 claims description 100
• 150000003839 salts Chemical class 0.000 claims description 73
• 230000003287 optical effect Effects 0.000 claims description 70
• 239000002253 acid Substances 0.000 claims description 65
• 150000004677 hydrates Chemical class 0.000 claims description 60
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 53
• 238000000034 method Methods 0.000 claims description 39
• -1 2 -cyclohexyl group Chemical group 0.000 claims description 34
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 23
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 15
• 125000000623 heterocyclic group Chemical group 0.000 claims description 14
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
• 125000005843 halogen group Chemical group 0.000 claims description 12
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• 125000004432 carbon atom Chemical group C* 0.000 claims description 11
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• 239000001257 hydrogen Substances 0.000 claims description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims description 9
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
• RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
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• 239000010948 rhodium Substances 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 6
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
• AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 6
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• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 5
• NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 claims description 5
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 125000001153 fluoro group Chemical group F* 0.000 claims description 5
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• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
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• 229910052703 rhodium Inorganic materials 0.000 claims description 4
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• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
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• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
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• DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 3
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• 208000037803 restenosis Diseases 0.000 claims description 3
• PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 2
• LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
• 206010022489 Insulin Resistance Diseases 0.000 claims description 2
• 208000007536 Thrombosis Diseases 0.000 claims description 2
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 206010061989 glomerulosclerosis Diseases 0.000 claims description 2
• 201000001421 hyperglycemia Diseases 0.000 claims description 2
• 231100000252 nontoxic Toxicity 0.000 claims description 2
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• 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 18
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
• AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 claims 2
• IPBPLHNLRKRLPJ-UHFFFAOYSA-N oxan-4-ylmethanamine Chemical compound NCC1CCOCC1 IPBPLHNLRKRLPJ-UHFFFAOYSA-N 0.000 claims 2
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
• LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 claims 1
• BHRVKIXDBWVUEH-UHFFFAOYSA-N 2-amino-n-cyclopentylacetamide Chemical compound NCC(=O)NC1CCCC1 BHRVKIXDBWVUEH-UHFFFAOYSA-N 0.000 claims 1
• 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 claims 1
• LGDWLHZEGZDFKO-UHFFFAOYSA-N 5-[4-(1-amino-2-cyclohexylethyl)-2,6-difluorobenzoyl]-2H-isoquinolin-1-one Chemical compound NC(CC1CCCCC1)C1=CC(=C(C(=O)C2=C3C=CNC(C3=CC=C2)=O)C(=C1)F)F LGDWLHZEGZDFKO-UHFFFAOYSA-N 0.000 claims 1
• 201000006474 Brain Ischemia Diseases 0.000 claims 1
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 1
• 208000019693 Lung disease Diseases 0.000 claims 1
• 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims 1
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 1
• 206010008118 cerebral infarction Diseases 0.000 claims 1
• ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 1
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
• 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 claims 1
• 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 abstract description 3
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