TW201206946A - Compounds for the reduction of beta-amyloid production - Google Patents

Info

Publication number

TW201206946A

TW201206946A TW100124501A TW100124501A TW201206946A TW 201206946 A TW201206946 A TW 201206946A TW 100124501 A TW100124501 A TW 100124501A TW 100124501 A TW100124501 A TW 100124501A TW 201206946 A TW201206946 A TW 201206946A

Authority

TW

Taiwan

Prior art keywords

cyclopenta

bridge

methyl

mmol

hexahydro

Prior art date

2010-07-15

Links

• Espacenet
• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims abstract description 200
• 238000004519 manufacturing process Methods 0.000 title claims abstract description 16
• 230000009467 reduction Effects 0.000 title description 12
• 102000013455 Amyloid beta-Peptides Human genes 0.000 title description 4
• 108010090849 Amyloid beta-Peptides Proteins 0.000 title description 4
• 150000003839 salts Chemical class 0.000 claims abstract description 31
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 25
• 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 claims abstract description 6
• 239000000203 mixture Substances 0.000 claims description 262
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 262
• 229910052757 nitrogen Inorganic materials 0.000 claims description 146
• -1 phenyl Chemical group 0.000 claims description 96
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 41
• 239000007789 gas Substances 0.000 claims description 38
• ADOBXTDBFNCOBN-UHFFFAOYSA-N 1-heptadecene Chemical compound CCCCCCCCCCCCCCCC=C ADOBXTDBFNCOBN-UHFFFAOYSA-N 0.000 claims description 34
• 125000000623 heterocyclic group Chemical group 0.000 claims description 31
• 125000000217 alkyl group Chemical group 0.000 claims description 23
• 229910052739 hydrogen Inorganic materials 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
• MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 16
• RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 15
• 125000003545 alkoxy group Chemical group 0.000 claims description 15
• RYDICHIKLKVOEJ-UHFFFAOYSA-N oxadiazepine Chemical compound O1C=CC=CN=N1 RYDICHIKLKVOEJ-UHFFFAOYSA-N 0.000 claims description 15
• 239000000843 powder Substances 0.000 claims description 14
• 239000001257 hydrogen Substances 0.000 claims description 13
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• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
• 239000001301 oxygen Chemical group 0.000 claims description 11
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 9
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• YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 8
• SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 8
• 201000008319 inclusion body myositis Diseases 0.000 claims description 8
• KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• 208000010877 cognitive disease Diseases 0.000 claims description 7
• 239000003085 diluting agent Substances 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 7
• DFNZMICWMCBMQR-UHFFFAOYSA-N oxatriazepane Chemical compound C1CNNNOC1 DFNZMICWMCBMQR-UHFFFAOYSA-N 0.000 claims description 7
• 239000000126 substance Substances 0.000 claims description 7
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 6
• 201000010374 Down Syndrome Diseases 0.000 claims description 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 208000002780 macular degeneration Diseases 0.000 claims description 6
• 208000027061 mild cognitive impairment Diseases 0.000 claims description 6
• CQDAMYNQINDRQC-UHFFFAOYSA-N oxatriazole Chemical compound C1=NN=NO1 CQDAMYNQINDRQC-UHFFFAOYSA-N 0.000 claims description 6
• 229910052707 ruthenium Inorganic materials 0.000 claims description 6
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 5
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 5
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
• 206010064930 age-related macular degeneration Diseases 0.000 claims description 5
• 210000004556 brain Anatomy 0.000 claims description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• 201000010099 disease Diseases 0.000 claims description 5
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
• 125000005843 halogen group Chemical group 0.000 claims description 5
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 5
• 108090000623 proteins and genes Proteins 0.000 claims description 5
• 150000003852 triazoles Chemical class 0.000 claims description 5
• KBUVKGMVZDAWOJ-UHFFFAOYSA-N 3h-oxathiazepine Chemical compound C=1C=COSNC=1 KBUVKGMVZDAWOJ-UHFFFAOYSA-N 0.000 claims description 4
• 241000124008 Mammalia Species 0.000 claims description 4
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
• NDJKXXJCMXVBJW-UHFFFAOYSA-N heptadecane Chemical compound CCCCCCCCCCCCCCCCC NDJKXXJCMXVBJW-UHFFFAOYSA-N 0.000 claims description 4
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• CCCMONHAUSKTEQ-UHFFFAOYSA-N octadecene Natural products CCCCCCCCCCCCCCCCC=C CCCMONHAUSKTEQ-UHFFFAOYSA-N 0.000 claims description 4
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
• 102000004169 proteins and genes Human genes 0.000 claims description 4
• NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 3
• 206010028980 Neoplasm Diseases 0.000 claims description 3
• 206010044688 Trisomy 21 Diseases 0.000 claims description 3
• 125000003342 alkenyl group Chemical group 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 229910052736 halogen Inorganic materials 0.000 claims description 3
• 150000002367 halogens Chemical class 0.000 claims description 3
• 150000002431 hydrogen Chemical class 0.000 claims description 3
• 125000002560 nitrile group Chemical group 0.000 claims description 3
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 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
• 229910052717 sulfur Chemical group 0.000 claims description 3
• 239000011593 sulfur Chemical group 0.000 claims description 3
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
• 201000011510 cancer Diseases 0.000 claims description 2
• ILAJTKAKMVQGNJ-UPHRSURJSA-N cyclohexadecene Chemical compound C1CCCCCCC\C=C/CCCCCC1 ILAJTKAKMVQGNJ-UPHRSURJSA-N 0.000 claims description 2
• 125000000524 functional group Chemical group 0.000 claims description 2
• 229910052727 yttrium Inorganic materials 0.000 claims description 2
• 206010067889 Dementia with Lewy bodies Diseases 0.000 claims 2
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 2
• 201000002832 Lewy body dementia Diseases 0.000 claims 2
• DCAYPVUWAIABOU-UHFFFAOYSA-N hexadecane Chemical compound CCCCCCCCCCCCCCCC DCAYPVUWAIABOU-UHFFFAOYSA-N 0.000 claims 2
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 1
• 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims 1
• IPZVVYCAEVTIQC-UHFFFAOYSA-N 1,2-diazacyclohexadecane Chemical compound N1NCCCCCCCCCCCCCC1 IPZVVYCAEVTIQC-UHFFFAOYSA-N 0.000 claims 1
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
• 101100447665 Mus musculus Gas2 gene Proteins 0.000 claims 1
• 240000007594 Oryza sativa Species 0.000 claims 1
• 235000007164 Oryza sativa Nutrition 0.000 claims 1
• 239000005864 Sulphur Substances 0.000 claims 1
• XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims 1
• 230000000747 cardiac effect Effects 0.000 claims 1
• 230000001351 cycling effect Effects 0.000 claims 1
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• HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims 1
• 229940067157 phenylhydrazine Drugs 0.000 claims 1
• 235000009566 rice Nutrition 0.000 claims 1
• 210000002784 stomach Anatomy 0.000 claims 1
• 229910021653 sulphate ion Inorganic materials 0.000 claims 1
• 125000001425 triazolyl group Chemical group 0.000 claims 1
• 150000003648 triterpenes Chemical class 0.000 claims 1
• 238000011282 treatment Methods 0.000 abstract description 12
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 572
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• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 165
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 156
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 88
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• 238000003818 flash chromatography Methods 0.000 description 46
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 43
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• 238000000034 method Methods 0.000 description 41
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