AU2011279412B2 - Compounds for the reduction of beta-amyloid production - Google Patents

Info

Publication number

AU2011279412B2

AU2011279412B2 AU2011279412A AU2011279412A AU2011279412B2 AU 2011279412 B2 AU2011279412 B2 AU 2011279412B2 AU 2011279412 A AU2011279412 A AU 2011279412A AU 2011279412 A AU2011279412 A AU 2011279412A AU 2011279412 B2 AU2011279412 B2 AU 2011279412B2

Authority

AU

Australia

Prior art keywords

cyclopenta

methyl

azeno

metheno

mmol

Prior art date

2010-07-15

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.)

Ceased

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 232
• 238000004519 manufacturing process Methods 0.000 title claims abstract description 16
• 230000009467 reduction Effects 0.000 title claims description 13
• 102000013455 Amyloid beta-Peptides Human genes 0.000 title description 2
• 108010090849 Amyloid beta-Peptides Proteins 0.000 title description 2
• 150000003839 salts Chemical class 0.000 claims abstract description 29
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 27
• 238000011282 treatment Methods 0.000 claims abstract description 12
• 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 7
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 213
• 239000000203 mixture Substances 0.000 claims description 155
• 229910052757 nitrogen Inorganic materials 0.000 claims description 111
• -1 18-(2,4-difluorophenyl)-7-(3-methyl-iH-1,2,4-triazol-1-yl) 10, 11,12,13,14,16,17,18-octahydro-5,2-(azeno)-8,4 (metheno)cyclopenta[h] [1,6,10,12]oxatriazacycloheptadecine Chemical compound 0.000 claims description 35
• BFEZZSRZXWNCOQ-UHFFFAOYSA-N N1=C2C(C=NC=CC=COC=CC=CC=3N=C1C=3)=CC=C2 Chemical compound N1=C2C(C=NC=CC=COC=CC=CC=3N=C1C=3)=CC=C2 BFEZZSRZXWNCOQ-UHFFFAOYSA-N 0.000 claims description 33
• 238000000034 method Methods 0.000 claims description 27
• 125000000217 alkyl group Chemical group 0.000 claims description 26
• 239000008194 pharmaceutical composition Substances 0.000 claims description 18
• MPJNYKXXSWCRRM-UHFFFAOYSA-N 1-oxa-2,3,4-triazacycloheptadeca-2,4,6,8,10,12,14,16-octaene Chemical compound C1=CC=CC=CC=NN=NOC=CC=CC=C1 MPJNYKXXSWCRRM-UHFFFAOYSA-N 0.000 claims description 16
• 125000003545 alkoxy group Chemical group 0.000 claims description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
• 125000001072 heteroaryl group Chemical group 0.000 claims description 14
• 229910052739 hydrogen Inorganic materials 0.000 claims description 14
• KEIIYOKPSKQJTB-UHFFFAOYSA-N 8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1,3(22),4,6,10,12,14(21),15,17,19-decaene Chemical compound N1=C2C(C=3N=CC=CCOC=4C=CC=C(N=C1N=3)C=4)=CC=C2 KEIIYOKPSKQJTB-UHFFFAOYSA-N 0.000 claims description 13
• 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 12
• 201000002832 Lewy body dementia Diseases 0.000 claims description 12
• 201000008319 inclusion body myositis Diseases 0.000 claims description 11
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 10
• 208000035475 disorder Diseases 0.000 claims description 10
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 9
• 125000005843 halogen group Chemical group 0.000 claims description 9
• NPGVJCMVNQBEDU-UHFFFAOYSA-N 1-oxa-6,10,12-triazacycloheptadeca-2,4,6,8,10,12,14,16-octaene Chemical compound C1=CC=NC=NC=CC=NC=CC=COC=C1 NPGVJCMVNQBEDU-UHFFFAOYSA-N 0.000 claims description 8
• QYMSJXKEHPYVSI-UHFFFAOYSA-N C1=CC=COC=CC=CC2=CC(=N2)N=C3C=CC=C3C=C1 Chemical compound C1=CC=COC=CC=CC2=CC(=N2)N=C3C=CC=C3C=C1 QYMSJXKEHPYVSI-UHFFFAOYSA-N 0.000 claims description 8
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
• FVFHZKZQBYHTKR-UHFFFAOYSA-N 1-oxa-2,3,4-triazacyclohexadeca-3,5,7,9,11,13,15-heptaene Chemical compound C=1C=CC=CC=CONN=NC=CC=CC=1 FVFHZKZQBYHTKR-UHFFFAOYSA-N 0.000 claims description 7
• 239000003085 diluting agent Substances 0.000 claims description 7
• 201000010374 Down Syndrome Diseases 0.000 claims description 6
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
• 239000001257 hydrogen Substances 0.000 claims description 6
• 208000002780 macular degeneration Diseases 0.000 claims description 6
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 239000001301 oxygen Chemical group 0.000 claims description 6
• JRWAWKIVAMGLJO-UHFFFAOYSA-N 8-oxa-2,12,19,20-tetrazatetracyclo[11.6.1.13,7.014,18]henicosa-1,3(21),4,6,9,11,13(20),14,16,18-decaene Chemical compound N1=C2C(C=3N=CC=COC=4C=CC=C(N=C1N=3)C=4)=CC=C2 JRWAWKIVAMGLJO-UHFFFAOYSA-N 0.000 claims description 5
• GOEKLYZPESSGDS-UHFFFAOYSA-N C1C=CC=CC2=NC(=NC3=CC(=CC=C3)O1)N=C4C2=CC=C4 Chemical compound C1C=CC=CC2=NC(=NC3=CC(=CC=C3)O1)N=C4C2=CC=C4 GOEKLYZPESSGDS-UHFFFAOYSA-N 0.000 claims description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
• 241000124008 Mammalia Species 0.000 claims description 5
• 206010064930 age-related macular degeneration Diseases 0.000 claims description 5
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
• 229910052799 carbon Inorganic materials 0.000 claims description 4
• 229910052736 halogen Inorganic materials 0.000 claims description 4
• 150000002367 halogens Chemical class 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
• YQACBOHOQUSMII-UHFFFAOYSA-N 1-oxa-4,7,11,13-tetrazacyclooctadeca-3,5,7,9,11,13,15,17-octaene Chemical compound O1CC=NC=CN=CC=CN=CN=CC=CC=C1 YQACBOHOQUSMII-UHFFFAOYSA-N 0.000 claims description 3
• HIFISDWFQAXNMP-UHFFFAOYSA-N 1-oxa-7,9,13-triazacyclooctadeca-3,5,7,9,11,13,15,17-octaene Chemical compound O1CC=CC=CN=CN=CC=CN=CC=CC=C1 HIFISDWFQAXNMP-UHFFFAOYSA-N 0.000 claims description 3
• AFJYYTUXRGZTLI-UHFFFAOYSA-N 13-methyl-6-(3-methyl-1,2,4-triazol-1-yl)-18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1CC=2C(=N3)N(C)CCCCOC(C(=CC=4)N5N=C(C)N=C5)=CC=4NC3=NC=2C1C1=CC=CC=C1 AFJYYTUXRGZTLI-UHFFFAOYSA-N 0.000 claims description 3
• UYQVMWNJHMWEFE-UHFFFAOYSA-N 13-methyl-6-(5-methyl-1,2,4-triazol-1-yl)-18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1CC=2C(=N3)N(C)CCCCOC(C(=CC=4)N5C(=NC=N5)C)=CC=4NC3=NC=2C1C1=CC=CC=C1 UYQVMWNJHMWEFE-UHFFFAOYSA-N 0.000 claims description 3
• JRJNMKOSTXFXCG-UHFFFAOYSA-N C1=CC2=NC3=NC(=C3)C=CC(=COC=CN=CC=CC2=C1)C#N Chemical compound C1=CC2=NC3=NC(=C3)C=CC(=COC=CN=CC=CC2=C1)C#N JRJNMKOSTXFXCG-UHFFFAOYSA-N 0.000 claims description 3
• DFDSMFRVLOODCR-UHFFFAOYSA-N C1C=CN=CC2=CC=CC2=NC=NC3=CC(=CC=C3)O1 Chemical compound C1C=CN=CC2=CC=CC2=NC=NC3=CC(=CC=C3)O1 DFDSMFRVLOODCR-UHFFFAOYSA-N 0.000 claims description 3
• 206010028980 Neoplasm Diseases 0.000 claims description 3
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
• 201000011510 cancer Diseases 0.000 claims description 3
• 125000002560 nitrile group Chemical group 0.000 claims description 3
• UZGLIIJVICEWHF-UHFFFAOYSA-N octogen Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)CN([N+]([O-])=O)C1 UZGLIIJVICEWHF-UHFFFAOYSA-N 0.000 claims description 3
• 229910052717 sulfur Chemical group 0.000 claims description 3
• 239000011593 sulfur Chemical group 0.000 claims description 3
• UNAHGQWUVWLYAS-UHFFFAOYSA-N 1,4-dioxa-7,11,13-triazacyclooctadeca-2,5,7,9,11,13,15,17-octaene Chemical compound O1C=COC=CN=CC=CN=CN=CC=CC=C1 UNAHGQWUVWLYAS-UHFFFAOYSA-N 0.000 claims description 2
• XXVMPTJGGYAODS-UHFFFAOYSA-N 1-oxa-2,3,4,5-tetrazacyclooctadeca-3,5,7,9,11,13,15,17-octaene Chemical compound O1NN=NN=CC=CC=CC=CC=CC=CC=C1 XXVMPTJGGYAODS-UHFFFAOYSA-N 0.000 claims description 2
• RPZTVJWNMAAMDR-UHFFFAOYSA-N 1-oxa-2,3,4-triazacyclooctadeca-3,5,7,9,11,13,15,17-octaene Chemical compound N1OC=CC=CC=CC=CC=CC=CC=CN=N1 RPZTVJWNMAAMDR-UHFFFAOYSA-N 0.000 claims description 2
• DYCBEOLLILVMRH-UHFFFAOYSA-N 18-(2,4-difluorophenyl)-13-methyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene-6-carbonitrile Chemical compound C1CC=2C(=N3)N(C)CCCCOC(C(=CC=4)C#N)=CC=4NC3=NC=2C1C1=CC=C(F)C=C1F DYCBEOLLILVMRH-UHFFFAOYSA-N 0.000 claims description 2
• JHTITZSJEVVJBF-UHFFFAOYSA-N 18-(4-fluorophenyl)-6-(3-methyl-1,2,4-triazol-1-yl)-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1=C(C=CC(=C1)C1C2=NC3=NC(=C2CC1)NCCCCOC1=C(C=CC(=C1)N3)N1C=NC(C)=N1)F JHTITZSJEVVJBF-UHFFFAOYSA-N 0.000 claims description 2
• GOQPGHPDMIWJAR-UHFFFAOYSA-N 18-phenyl-8-oxa-2,20,21-triazatetracyclo[12.6.1.13,7.015,19]docosa-1(21),3(22),4,6,14,19-hexaene-6-carbonitrile Chemical compound C1CC=2C(=N3)CCCCCOC(=C4)C(C#N)=CC=C4NC3=NC=2C1C1=CC=CC=C1 GOQPGHPDMIWJAR-UHFFFAOYSA-N 0.000 claims description 2
• RYMSIBOTNUIQAP-UHFFFAOYSA-N 6-(3-methyl-1,2,4-triazol-1-yl)-18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound N1=C(C)N=CN1C1=CC=C(N2)C=C1OCCCCNC1=NC2=NC2=C1CCC2C1=CC=CC=C1 RYMSIBOTNUIQAP-UHFFFAOYSA-N 0.000 claims description 2
• VRXLUWYIOGBPCL-UHFFFAOYSA-N 6-(3-methyl-1,2,4-triazol-1-yl)-18-phenyl-8-oxa-2,20,21-triazatetracyclo[12.6.1.13,7.015,19]docosa-1(21),3(22),4,6,14,19-hexaene Chemical compound N1=C(C)N=CN1C1=CC=C(N2)C=C1OCCCCCC1=NC2=NC2=C1CCC2C1=CC=CC=C1 VRXLUWYIOGBPCL-UHFFFAOYSA-N 0.000 claims description 2
• FXRRQMQWRDATBM-UHFFFAOYSA-N 6-(4-chloroimidazol-1-yl)-18-(2,4-difluorophenyl)-13-methyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound C1CC=2C(=N3)N(C)CCCCOC(C(=CC=4)N5C=C(Cl)N=C5)=CC=4NC3=NC=2C1C1=CC=C(F)C=C1F FXRRQMQWRDATBM-UHFFFAOYSA-N 0.000 claims description 2
• QJDUZIDYDFIENI-UHFFFAOYSA-N 6-(5-methyl-1,2,4-triazol-1-yl)-18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene Chemical compound CC1=NC=NN1C1=CC=C(N2)C=C1OCCCCNC1=NC2=NC2=C1CCC2C1=CC=CC=C1 QJDUZIDYDFIENI-UHFFFAOYSA-N 0.000 claims description 2
• XEMUWSNMAIGMSJ-UHFFFAOYSA-N C(C1)CC(N2)=C1C(NCCCCO1)=NC2=NC2=CC=CC1=C2 Chemical compound C(C1)CC(N2)=C1C(NCCCCO1)=NC2=NC2=CC=CC1=C2 XEMUWSNMAIGMSJ-UHFFFAOYSA-N 0.000 claims description 2
• BQNYERJCIISDAT-UHFFFAOYSA-N C1C=CC=NC=C2C=CC=C2N=C3N=C4C=CC(=CC4=N3)O1 Chemical compound C1C=CC=NC=C2C=CC=C2N=C3N=C4C=CC(=CC4=N3)O1 BQNYERJCIISDAT-UHFFFAOYSA-N 0.000 claims 16
• XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims 12
• BBTCVLLKSAWIGB-UHFFFAOYSA-N 1-oxa-2,3-diazacycloheptadeca-2,4,6,8,10,12,14,16-octaene Chemical compound C1=CC=CC=CC=CON=NC=CC=CC=C1 BBTCVLLKSAWIGB-UHFFFAOYSA-N 0.000 claims 3
• FHGYDTGGUNOESO-UHFFFAOYSA-N 18-(4-fluorophenyl)-10-hydroxy-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene-6-carbonitrile Chemical compound N1C(C=2)=CC=C(C#N)C=2OCC(O)CCNC(C=2CC3)=NC1=NC=2C3C1=CC=C(F)C=C1 FHGYDTGGUNOESO-UHFFFAOYSA-N 0.000 claims 1
• QSMJRYHHVJROJR-UHFFFAOYSA-N 18-phenyl-8-oxa-2,13,20,21-tetrazatetracyclo[12.6.1.13,7.015,19]docosa-1(20),3(22),4,6,14(21),15(19)-hexaene-6-carbonitrile Chemical compound C1CC=2C(=N3)NCCCCOC(=C4)C(C#N)=CC=C4NC3=NC=2C1C1=CC=CC=C1 QSMJRYHHVJROJR-UHFFFAOYSA-N 0.000 claims 1
• MLXTUDUHXXWHIQ-UHFFFAOYSA-N 8-oxa-2,11,14,21,22-pentazatetracyclo[13.6.1.13,7.016,20]tricosa-1,3(23),4,6,9,11,13,15(22),16,18,20-undecaene Chemical compound N1=C2C(C=3N=CC=NC=COC=4C=CC=C(N=C1N=3)C=4)=CC=C2 MLXTUDUHXXWHIQ-UHFFFAOYSA-N 0.000 claims 1
• 230000001149 cognitive effect Effects 0.000 claims 1
• DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 abstract 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 435
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• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 191
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• 239000000377 silicon dioxide Substances 0.000 description 166
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