JP2010539180A - ヒスタミン３拮抗薬としてのイソキノリニルおよびイソインドリニル誘導体 - Google Patents

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Publication number

JP2010539180A

JP2010539180A JP2010524978A JP2010524978A JP2010539180A JP 2010539180 A JP2010539180 A JP 2010539180A JP 2010524978 A JP2010524978 A JP 2010524978A JP 2010524978 A JP2010524978 A JP 2010524978A JP 2010539180 A JP2010539180 A JP 2010539180A

Authority

JP

Japan

Prior art keywords

pyrrolidin

ylethyl

oxo

ethyl

tetrahydroisoquinolin

Prior art date

2007-09-12

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.)

Withdrawn

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• NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 title claims abstract description 42
• 229960001340 histamine Drugs 0.000 title claims abstract description 21
• 239000005557 antagonist Substances 0.000 title description 7
• 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 title description 3
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 236
• -1 cycloheteroalkyl Chemical group 0.000 claims description 145
• 238000000034 method Methods 0.000 claims description 101
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 39
• 150000003839 salts Chemical class 0.000 claims description 37
• 208000010877 cognitive disease Diseases 0.000 claims description 32
• 229910052757 nitrogen Inorganic materials 0.000 claims description 31
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
• 125000000217 alkyl group Chemical group 0.000 claims description 25
• 208000024827 Alzheimer disease Diseases 0.000 claims description 24
• 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 24
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 24
• 125000003118 aryl group Chemical group 0.000 claims description 21
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
• 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 20
• 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 20
• 125000001072 heteroaryl group Chemical group 0.000 claims description 20
• 229910052760 oxygen Inorganic materials 0.000 claims description 18
• 208000035475 disorder Diseases 0.000 claims description 16
• 206010012289 Dementia Diseases 0.000 claims description 15
• 201000000980 schizophrenia Diseases 0.000 claims description 15
• 229910052717 sulfur Inorganic materials 0.000 claims description 14
• 208000018737 Parkinson disease Diseases 0.000 claims description 13
• 230000000694 effects Effects 0.000 claims description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
• 125000001188 haloalkyl group Chemical group 0.000 claims description 13
• 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 13
• 125000005842 heteroatom Chemical group 0.000 claims description 12
• 229910052736 halogen Inorganic materials 0.000 claims description 10
• 150000002367 halogens Chemical class 0.000 claims description 10
• QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 9
• 229940095102 methyl benzoate Drugs 0.000 claims description 9
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
• 208000027061 mild cognitive impairment Diseases 0.000 claims description 9
• 239000002904 solvent Substances 0.000 claims description 9
• DSPDNROSUXQSCT-UHFFFAOYSA-N 4-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-3,4-dihydroisoquinolin-6-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(C(=O)N(CCN2CCCC2)CC2)C2=C1 DSPDNROSUXQSCT-UHFFFAOYSA-N 0.000 claims description 8
• 208000023105 Huntington disease Diseases 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 230000006870 function Effects 0.000 claims description 7
• 229910052739 hydrogen Inorganic materials 0.000 claims description 7
• 206010027175 memory impairment Diseases 0.000 claims description 7
• 239000002253 acid Substances 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
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• 125000004429 atom Chemical group 0.000 claims description 5
• 125000002619 bicyclic group Chemical group 0.000 claims description 5
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• ZOYRJBIULHDHMS-UHFFFAOYSA-N n-methoxy-n-methyl-4-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-3,4-dihydroisoquinolin-6-yl]benzamide Chemical compound C1=CC(C(=O)N(C)OC)=CC=C1C1=CC=C(C(=O)N(CCN2CCCC2)CC2)C2=C1 ZOYRJBIULHDHMS-UHFFFAOYSA-N 0.000 claims description 5
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
• XPZHIEBBPQVJCT-HXUWFJFHSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-6-[4-(pyrrolidine-1-carbonyl)phenoxy]-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(OC=3C=CC(=CC=3)C(=O)N3CCCC3)C=C2CC1 XPZHIEBBPQVJCT-HXUWFJFHSA-N 0.000 claims description 4
• 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 4
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
• PESOUNLSPHQJGL-INIZCTEOSA-N 6-(4-fluorophenyl)-2-[2-[(2s)-2-methylpyrrolidin-1-yl]ethyl]-3,4-dihydroisoquinolin-1-one Chemical compound C[C@H]1CCCN1CCN1C(=O)C2=CC=C(C=3C=CC(F)=CC=3)C=C2CC1 PESOUNLSPHQJGL-INIZCTEOSA-N 0.000 claims description 4
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• 230000006999 cognitive decline Effects 0.000 claims description 4
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
• LZTSCEYDCZBRCJ-UHFFFAOYSA-N 1,2-dihydro-1,2,4-triazol-3-one Chemical class OC=1N=CNN=1 LZTSCEYDCZBRCJ-UHFFFAOYSA-N 0.000 claims description 3
• 150000005072 1,3,4-oxadiazoles Chemical class 0.000 claims description 3
• DYWLJRPIZPWGET-QGZVFWFLSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-6-(1-oxo-3,4-dihydro-2h-isoquinolin-6-yl)-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(C=3C=C4CCNC(=O)C4=CC=3)C=C2CC1 DYWLJRPIZPWGET-QGZVFWFLSA-N 0.000 claims description 3
• RJJREVXLBPEJNJ-UHFFFAOYSA-N 2-methyl-6-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-3,4-dihydroisoquinolin-6-yl]-3,4-dihydroisoquinolin-1-one Chemical compound C=1C=C2C(=O)N(C)CCC2=CC=1C(C=C1CC2)=CC=C1C(=O)N2CCN1CCCC1 RJJREVXLBPEJNJ-UHFFFAOYSA-N 0.000 claims description 3
• VKDSWJFAIIVEQX-MRXNPFEDSA-N 4-[2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-1-oxo-3h-isoindol-5-yl]benzonitrile Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(C=3C=CC(=CC=3)C#N)C=C2C1 VKDSWJFAIIVEQX-MRXNPFEDSA-N 0.000 claims description 3
• 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 description 3
• XVVITBZYEYKSAH-UHFFFAOYSA-N 5-(benzimidazol-1-ylmethyl)-2-(2-pyrrolidin-1-ylethyl)-3h-isoindol-1-one Chemical compound C1C2=CC(CN3C4=CC=CC=C4N=C3)=CC=C2C(=O)N1CCN1CCCC1 XVVITBZYEYKSAH-UHFFFAOYSA-N 0.000 claims description 3
• IXGOGVFDYFVFOF-UHFFFAOYSA-N 6-[4-(cyclopropanecarbonyl)phenyl]-2-(2-pyrrolidin-1-ylethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C=1C=C(C=2C=C3CCN(CCN4CCCC4)C(=O)C3=CC=2)C=CC=1C(=O)C1CC1 IXGOGVFDYFVFOF-UHFFFAOYSA-N 0.000 claims description 3
• IWUGHHQMBCOMOV-UHFFFAOYSA-N 6-indazol-1-yl-2-(2-pyrrolidin-1-ylethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C1CC2=CC(N3C4=CC=CC=C4C=N3)=CC=C2C(=O)N1CCN1CCCC1 IWUGHHQMBCOMOV-UHFFFAOYSA-N 0.000 claims description 3
• 208000020925 Bipolar disease Diseases 0.000 claims description 3
• 208000020406 Creutzfeldt Jacob disease Diseases 0.000 claims description 3
• 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 claims description 3
• 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 3
• 206010012218 Delirium Diseases 0.000 claims description 3
• 201000010374 Down Syndrome 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
• 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 3
• 208000030886 Traumatic Brain injury Diseases 0.000 claims description 3
• 210000001766 X chromosome Anatomy 0.000 claims description 3
• 208000028683 bipolar I disease Diseases 0.000 claims description 3
• WZHAQWFZACLGKI-UHFFFAOYSA-N n-cyclopentyl-4-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-3,4-dihydroisoquinolin-6-yl]benzamide Chemical compound C=1C=C(C=2C=C3CCN(CCN4CCCC4)C(=O)C3=CC=2)C=CC=1C(=O)NC1CCCC1 WZHAQWFZACLGKI-UHFFFAOYSA-N 0.000 claims description 3
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• IIQVHLRPDRFQHC-UHFFFAOYSA-N 1-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-3,4-dihydroisoquinolin-6-yl]indole-5-carbonitrile Chemical compound C1CC2=CC(N3C4=CC=C(C=C4C=C3)C#N)=CC=C2C(=O)N1CCN1CCCC1 IIQVHLRPDRFQHC-UHFFFAOYSA-N 0.000 claims description 2
• YFURTEYAEPSLFX-UHFFFAOYSA-N 2-(2-pyrrolidin-1-ylethyl)-6-[3-(trifluoromethoxy)phenyl]-3,4-dihydroisoquinolin-1-one Chemical compound FC(F)(F)OC1=CC=CC(C=2C=C3CCN(CCN4CCCC4)C(=O)C3=CC=2)=C1 YFURTEYAEPSLFX-UHFFFAOYSA-N 0.000 claims description 2
• YGDXRYIZHALWOY-UHFFFAOYSA-N 2-(2-pyrrolidin-1-ylethyl)-6-[3-(trifluoromethyl)phenyl]-3,4-dihydroisoquinolin-1-one Chemical compound FC(F)(F)C1=CC=CC(C=2C=C3CCN(CCN4CCCC4)C(=O)C3=CC=2)=C1 YGDXRYIZHALWOY-UHFFFAOYSA-N 0.000 claims description 2
• SXUZRGLZTPXKSU-UHFFFAOYSA-N 2-(2-pyrrolidin-1-ylethyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-1h-isoquinoline Chemical compound C1=CC(OC(F)(F)F)=CC=C1C1=CC=C(CN(CCN2CCCC2)CC2)C2=C1 SXUZRGLZTPXKSU-UHFFFAOYSA-N 0.000 claims description 2
• UZARNTGJNZJLMB-UHFFFAOYSA-N 2-(2-pyrrolidin-1-ylethyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroisoquinolin-1-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1C1=CC=C(C(=O)N(CCN2CCCC2)CC2)C2=C1 UZARNTGJNZJLMB-UHFFFAOYSA-N 0.000 claims description 2
• IZGHSNVQGBODFP-UHFFFAOYSA-N 2-(2-pyrrolidin-1-ylethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinolin-1-one Chemical compound C1=CC(C(F)(F)F)=CC=C1C1=CC=C(C(=O)N(CCN2CCCC2)CC2)C2=C1 IZGHSNVQGBODFP-UHFFFAOYSA-N 0.000 claims description 2
• VCCZQTCRRYEOMQ-UHFFFAOYSA-N 2-[2-(azepan-1-yl)ethyl]-6-(4-fluorophenyl)-3,4-dihydro-1h-isoquinoline Chemical compound C1=CC(F)=CC=C1C1=CC=C(CN(CCN2CCCCCC2)CC2)C2=C1 VCCZQTCRRYEOMQ-UHFFFAOYSA-N 0.000 claims description 2
• ULDQVOFOHYQSEB-UHFFFAOYSA-N 2-[2-(azepan-1-yl)ethyl]-6-(4-fluorophenyl)-3,4-dihydroisoquinolin-1-one Chemical compound C1=CC(F)=CC=C1C1=CC=C(C(=O)N(CCN2CCCCCC2)CC2)C2=C1 ULDQVOFOHYQSEB-UHFFFAOYSA-N 0.000 claims description 2
• LHOPPDSAKXYMGM-UHFFFAOYSA-N 2-[2-(azepan-1-yl)ethyl]-6-piperidin-1-yl-3,4-dihydroisoquinolin-1-one Chemical compound C1CC2=CC(N3CCCCC3)=CC=C2C(=O)N1CCN1CCCCCC1 LHOPPDSAKXYMGM-UHFFFAOYSA-N 0.000 claims description 2
• LVGUHWADRXKKTN-MRXNPFEDSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-1-oxo-n-pyridin-4-yl-3,4-dihydroisoquinoline-6-carboxamide Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(C(=O)NC=3C=CN=CC=3)C=C2CC1 LVGUHWADRXKKTN-MRXNPFEDSA-N 0.000 claims description 2
• VIXLFZWEFXGIRZ-LJQANCHMSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-5-[4-(pyrrolidine-1-carbonyl)phenyl]-3h-isoindol-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(C=3C=CC(=CC=3)C(=O)N3CCCC3)C=C2C1 VIXLFZWEFXGIRZ-LJQANCHMSA-N 0.000 claims description 2
• XNIIGFMTISXHOP-QGZVFWFLSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-6-(piperidine-1-carbonyl)-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(C(=O)N3CCCCC3)C=C2CC1 XNIIGFMTISXHOP-QGZVFWFLSA-N 0.000 claims description 2
• DOZZMXWYOSFCSK-MRXNPFEDSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-6-(pyrrolidine-1-carbonyl)-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(C(=O)N3CCCC3)C=C2CC1 DOZZMXWYOSFCSK-MRXNPFEDSA-N 0.000 claims description 2
• CGMNEQRSMXPAEO-HXUWFJFHSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-6-[4-(morpholine-4-carbonyl)phenyl]-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(C=3C=CC(=CC=3)C(=O)N3CCOCC3)C=C2CC1 CGMNEQRSMXPAEO-HXUWFJFHSA-N 0.000 claims description 2
• RWVLKSWAEQZIHC-OAQYLSRUSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-6-[4-(piperidine-1-carbonyl)phenyl]-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(C=3C=CC(=CC=3)C(=O)N3CCCCC3)C=C2CC1 RWVLKSWAEQZIHC-OAQYLSRUSA-N 0.000 claims description 2
• SPKOQCHHYOCMGR-HXUWFJFHSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-6-[4-(pyrrolidine-1-carbonyl)phenyl]-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(C=3C=CC(=CC=3)C(=O)N3CCCC3)C=C2CC1 SPKOQCHHYOCMGR-HXUWFJFHSA-N 0.000 claims description 2
• OCEASSQDJLNZSQ-QGZVFWFLSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-6-piperidin-1-yl-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(N3CCCCC3)C=C2CC1 OCEASSQDJLNZSQ-QGZVFWFLSA-N 0.000 claims description 2
• BCFUWSDYWOXETI-MRXNPFEDSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-6-pyrrolidin-1-yl-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(N3CCCC3)C=C2CC1 BCFUWSDYWOXETI-MRXNPFEDSA-N 0.000 claims description 2
• HJYQEGBJLDVMGC-HXUWFJFHSA-N 2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-7-[4-(pyrrolidine-1-carbonyl)phenyl]-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC(C=3C=CC(=CC=3)C(=O)N3CCCC3)=CC=C2CC1 HJYQEGBJLDVMGC-HXUWFJFHSA-N 0.000 claims description 2
• 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
• PPMUILQUJWTJIP-GOSISDBHSA-N 2-methyl-6-[2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-3,4-dihydroisoquinolin-1-one Chemical compound C[C@@H]1CCCN1CCN1C(=O)C2=CC=C(C=3C=C4CCN(C)C(=O)C4=CC=3)C=C2CC1 PPMUILQUJWTJIP-GOSISDBHSA-N 0.000 claims description 2
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• XVSGKDREUJXSJI-UHFFFAOYSA-N 4-[1-oxo-2-(3-pyrrolidin-1-ylpropyl)-3,4-dihydroisoquinolin-6-yl]benzonitrile Chemical compound C1CC2=CC(C=3C=CC(=CC=3)C#N)=CC=C2C(=O)N1CCCN1CCCC1 XVSGKDREUJXSJI-UHFFFAOYSA-N 0.000 claims description 2
• GEKDFQFAAHBUSW-QGZVFWFLSA-N 4-[2-[2-[(2r)-2-methylpyrrolidin-1-yl]ethyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]benzonitrile Chemical compound C[C@@H]1CCCN1CCN1C(=O)C(C=CC=C2C=3C=CC(=CC=3)C#N)=C2CC1 GEKDFQFAAHBUSW-QGZVFWFLSA-N 0.000 claims description 2
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