TW200927114A - Isoquinolinyl and isoindolinyl derivatives as histamine-3 antagonists - Google Patents

Info

Publication number

TW200927114A

TW200927114A TW097135281A TW97135281A TW200927114A TW 200927114 A TW200927114 A TW 200927114A TW 097135281 A TW097135281 A TW 097135281A TW 97135281 A TW97135281 A TW 97135281A TW 200927114 A TW200927114 A TW 200927114A

Authority

TW

Taiwan

Prior art keywords

ethyl

ylethyl

pyrrolidin

oxy

phenyl

Prior art date

2007-09-12

Links

• Espacenet
• Global Dossier
• Discuss

• 239000005557 antagonist Substances 0.000 title description 5
• 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 title 1
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 199
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 144
• -1 cycloheteroalkyl Chemical group 0.000 claims description 124
• 238000000034 method Methods 0.000 claims description 113
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 90
• 238000002360 preparation method Methods 0.000 claims description 74
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 65
• OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 61
• 150000003839 salts Chemical class 0.000 claims description 40
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 38
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 36
• 125000000217 alkyl group Chemical group 0.000 claims description 33
• 239000002253 acid Substances 0.000 claims description 31
• 208000010877 cognitive disease Diseases 0.000 claims description 28
• 150000002576 ketones Chemical class 0.000 claims description 26
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 25
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
• 208000024827 Alzheimer disease Diseases 0.000 claims description 22
• 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 22
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 125000003118 aryl group Chemical group 0.000 claims description 21
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 20
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
• 125000001072 heteroaryl group Chemical group 0.000 claims description 20
• 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 17
• 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 17
• 238000006243 chemical reaction Methods 0.000 claims description 17
• 201000010099 disease Diseases 0.000 claims description 17
• 201000000980 schizophrenia Diseases 0.000 claims description 16
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 13
• 206010012289 Dementia Diseases 0.000 claims description 12
• 208000018737 Parkinson disease Diseases 0.000 claims description 12
• 125000004429 atom Chemical group 0.000 claims description 12
• 239000007789 gas Substances 0.000 claims description 12
• 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 12
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
• 239000001257 hydrogen Substances 0.000 claims description 11
• 229910052739 hydrogen Inorganic materials 0.000 claims description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
• UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 10
• YWPMKTWUFVOFPL-UHFFFAOYSA-N 3,4-dihydro-2h-isoquinolin-1-one Chemical compound C1=CC=C2C(=O)NCCC2=C1 YWPMKTWUFVOFPL-UHFFFAOYSA-N 0.000 claims description 10
• 239000000126 substance Substances 0.000 claims description 10
• 208000000044 Amnesia Diseases 0.000 claims description 9
• QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 9
• 125000005842 heteroatom Chemical group 0.000 claims description 9
• 208000027061 mild cognitive impairment Diseases 0.000 claims description 9
• 208000023105 Huntington disease Diseases 0.000 claims description 8
• AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 8
• 229910052757 nitrogen Inorganic materials 0.000 claims description 8
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
• 239000002904 solvent Substances 0.000 claims description 8
• 125000003342 alkenyl group Chemical group 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 230000006870 function Effects 0.000 claims description 7
• IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 claims description 6
• 208000026139 Memory disease Diseases 0.000 claims description 6
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
• 125000000304 alkynyl group Chemical group 0.000 claims description 6
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 6
• 229910052736 halogen Inorganic materials 0.000 claims description 6
• 150000002367 halogens Chemical group 0.000 claims description 6
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
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• 201000004810 Vascular dementia Diseases 0.000 claims description 5
• 125000002619 bicyclic group Chemical group 0.000 claims description 5
• 239000003795 chemical substances by application Substances 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
• 229940067157 phenylhydrazine Drugs 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• GWRSATNRNFYMDI-UHFFFAOYSA-N 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound FC=1C=C(NC=2N=C3N(C4CCCC4)CC(F)(F)C(=O)N(C)C3=CN=2)C(OC)=CC=1C(=O)NC1CCN(C)CC1 GWRSATNRNFYMDI-UHFFFAOYSA-N 0.000 claims description 4
• 208000031091 Amnestic disease Diseases 0.000 claims description 4
• 208000012239 Developmental disease Diseases 0.000 claims description 4
• 230000006986 amnesia Effects 0.000 claims description 4
• MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 4
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
• 125000004802 cyanophenyl group Chemical group 0.000 claims description 4
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
• 125000001188 haloalkyl group Chemical group 0.000 claims description 4
• 206010027175 memory impairment Diseases 0.000 claims description 4
• HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 4
• 208000024891 symptom Diseases 0.000 claims description 4
• VPKAHUMPZYVNIV-UHFFFAOYSA-N 1,4-dihydroisoquinoline Chemical compound C1=CC=C2CC=NCC2=C1 VPKAHUMPZYVNIV-UHFFFAOYSA-N 0.000 claims description 3
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 3
• GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims description 3
• 208000020925 Bipolar disease Diseases 0.000 claims description 3
• 206010012218 Delirium Diseases 0.000 claims description 3
• 201000011240 Frontotemporal dementia Diseases 0.000 claims description 3
• 206010019196 Head injury Diseases 0.000 claims description 3
• 206010033864 Paranoia Diseases 0.000 claims description 3
• 208000027099 Paranoid disease Diseases 0.000 claims description 3
• 239000004098 Tetracycline Substances 0.000 claims description 3
• 208000030886 Traumatic Brain injury Diseases 0.000 claims description 3
• 208000028683 bipolar I disease Diseases 0.000 claims description 3
• 230000006999 cognitive decline Effects 0.000 claims description 3
• 230000006984 memory degeneration Effects 0.000 claims description 3
• 208000023060 memory loss Diseases 0.000 claims description 3
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 3
• 238000001356 surgical procedure Methods 0.000 claims description 3
• 229960002180 tetracycline Drugs 0.000 claims description 3
• 230000009529 traumatic brain injury Effects 0.000 claims description 3
• RGHPCLZJAFCTIK-RXMQYKEDSA-N (R)-2-methylpyrrolidine Chemical compound C[C@@H]1CCCN1 RGHPCLZJAFCTIK-RXMQYKEDSA-N 0.000 claims description 2
• IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 claims description 2
• AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 2
• RGHPCLZJAFCTIK-UHFFFAOYSA-N 2-methylpyrrolidine Chemical compound CC1CCCN1 RGHPCLZJAFCTIK-UHFFFAOYSA-N 0.000 claims description 2
• BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-metylindole Natural products C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 claims description 2
• 201000002832 Lewy body dementia Diseases 0.000 claims description 2
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• 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 2
• RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 2
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• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• WGLUNLJVYNJMBU-UHFFFAOYSA-N n-[2-(dimethylamino)ethyl]-n-[(3-methyl-1-oxo-2,4-dihydroisoquinolin-3-yl)methyl]decanamide Chemical compound C1=CC=C2C(=O)NC(CN(CCN(C)C)C(=O)CCCCCCCCC)(C)CC2=C1 WGLUNLJVYNJMBU-UHFFFAOYSA-N 0.000 claims description 2
• 239000002689 soil Substances 0.000 claims description 2
• XREDBMQNKAWFGA-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-isoindole Chemical compound C1=CCC2CNCC2=C1 XREDBMQNKAWFGA-UHFFFAOYSA-N 0.000 claims 4
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims 3
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• OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims 1
• CRLKPAFRIQSZIQ-QGZVFWFLSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-6-pyrrolidin-1-yl-3,4-dihydro-1h-isoquinoline Chemical compound C[C@@H]1CCCN1CCN1CC2=CC=C(N3CCCC3)C=C2CC1 CRLKPAFRIQSZIQ-QGZVFWFLSA-N 0.000 claims 1
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• DKFXEXRXJSDLGU-UHFFFAOYSA-N 4-[[1-oxo-2-(2-pyrrolidin-1-ylethyl)-3,4-dihydroisoquinolin-6-yl]oxy]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OC1=CC=C(C(=O)N(CCN2CCCC2)CC2)C2=C1 DKFXEXRXJSDLGU-UHFFFAOYSA-N 0.000 claims 1
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• SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims 1
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