TW201030002A - Bicyclic compounds for the reduction of beta-amyloid production - Google Patents

Info

Publication number

TW201030002A

TW201030002A TW098146451A TW98146451A TW201030002A TW 201030002 A TW201030002 A TW 201030002A TW 098146451 A TW098146451 A TW 098146451A TW 98146451 A TW98146451 A TW 98146451A TW 201030002 A TW201030002 A TW 201030002A

Authority

TW

Taiwan

Prior art keywords

phenyl

amine

tetrahydro

group

triazolo

Prior art date

2009-01-16

Links

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• 238000004519 manufacturing process Methods 0.000 title claims abstract description 9
• 230000009467 reduction Effects 0.000 title claims description 7
• 125000002619 bicyclic group Chemical group 0.000 title description 3
• 102000013455 Amyloid beta-Peptides Human genes 0.000 title 1
• 108010090849 Amyloid beta-Peptides Proteins 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 98
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 26
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 277
• -1 hydroxy, methylamino Chemical group 0.000 claims description 189
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 129
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 123
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 102
• 239000007789 gas Substances 0.000 claims description 90
• 229910052757 nitrogen Inorganic materials 0.000 claims description 77
• 125000000217 alkyl group Chemical group 0.000 claims description 61
• 125000003545 alkoxy group Chemical group 0.000 claims description 60
• 229910052739 hydrogen Inorganic materials 0.000 claims description 55
• 239000001257 hydrogen Substances 0.000 claims description 54
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 48
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 43
• 125000001424 substituent group Chemical group 0.000 claims description 43
• 150000003839 salts Chemical class 0.000 claims description 41
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 34
• 150000001412 amines Chemical class 0.000 claims description 34
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 28
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
• 125000004076 pyridyl group Chemical group 0.000 claims description 25
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 21
• CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 claims description 18
• 125000005843 halogen group Chemical group 0.000 claims description 17
• 125000001072 heteroaryl group Chemical group 0.000 claims description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims description 17
• ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 16
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 16
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 13
• 239000004305 biphenyl Substances 0.000 claims description 13
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
• 125000003277 amino group Chemical group 0.000 claims description 11
• 125000003118 aryl group Chemical group 0.000 claims description 11
• 125000002883 imidazolyl group Chemical group 0.000 claims description 11
• 229910052717 sulfur Inorganic materials 0.000 claims description 11
• 239000011593 sulfur Substances 0.000 claims description 11
• 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims description 10
• 125000003282 alkyl amino group Chemical group 0.000 claims description 10
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
• 239000007983 Tris buffer Substances 0.000 claims description 9
• 239000000126 substance Substances 0.000 claims description 9
• 150000003852 triazoles Chemical class 0.000 claims description 9
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 8
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
• 125000001425 triazolyl group Chemical group 0.000 claims description 8
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 7
• 206010012289 Dementia Diseases 0.000 claims description 6
• 229910052736 halogen Inorganic materials 0.000 claims description 6
• 150000002367 halogens Chemical class 0.000 claims description 6
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 6
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 6
• 150000003573 thiols Chemical class 0.000 claims description 6
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 5
• 201000010374 Down Syndrome Diseases 0.000 claims description 5
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
• 206010044688 Trisomy 21 Diseases 0.000 claims description 5
• 230000032683 aging Effects 0.000 claims description 5
• 125000005265 dialkylamine group Chemical group 0.000 claims description 5
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
• 125000000524 functional group Chemical group 0.000 claims description 5
• 125000005842 heteroatom Chemical group 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 239000001301 oxygen Substances 0.000 claims description 5
• 229910021653 sulphate ion Inorganic materials 0.000 claims description 5
• AFBBKYQYNPNMAT-UHFFFAOYSA-N 1h-1,2,4-triazol-1-ium-3-thiolate Chemical compound SC=1N=CNN=1 AFBBKYQYNPNMAT-UHFFFAOYSA-N 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 4
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
• 206010036790 Productive cough Diseases 0.000 claims description 4
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
• 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 239000000796 flavoring agent Substances 0.000 claims description 4
• IPTBMHRWOVCERL-UHFFFAOYSA-N heptadec-1-en-2-amine Chemical compound CCCCCCCCCCCCCCCC(N)=C IPTBMHRWOVCERL-UHFFFAOYSA-N 0.000 claims description 4
• 201000008319 inclusion body myositis Diseases 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 150000002923 oximes Chemical class 0.000 claims description 4
• 208000024794 sputum Diseases 0.000 claims description 4
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
• 229910052801 chlorine Inorganic materials 0.000 claims description 3
• 208000010877 cognitive disease Diseases 0.000 claims description 3
• 229910052731 fluorine Inorganic materials 0.000 claims description 3
• 239000011737 fluorine Substances 0.000 claims description 3
• 125000001041 indolyl group Chemical group 0.000 claims description 3
• 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
• 208000011580 syndromic disease Diseases 0.000 claims description 3
• 150000003648 triterpenes Chemical class 0.000 claims description 3
• GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 claims description 2
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 2
• 241000124008 Mammalia Species 0.000 claims description 2
• 229910052786 argon Inorganic materials 0.000 claims description 2
• 125000004429 atom Chemical group 0.000 claims description 2
• 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• 125000004122 cyclic group Chemical group 0.000 claims description 2
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
• 125000006005 fluoroethoxy group Chemical group 0.000 claims description 2
• 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
• PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
• 210000003802 sputum Anatomy 0.000 claims description 2
• 229930191535 trisporin Natural products 0.000 claims description 2
• XXTSLITVQROIQO-UHFFFAOYSA-N hept-1-en-2-amine Chemical compound CCCCCC(N)=C XXTSLITVQROIQO-UHFFFAOYSA-N 0.000 claims 4
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims 2
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims 2
• QSJNAFJALFWFMT-UHFFFAOYSA-N meridine Chemical compound N1C=CC(=O)C2=C1C(=O)C1=NC=CC3=C(C=CC=C4)C4=NC2=C13 QSJNAFJALFWFMT-UHFFFAOYSA-N 0.000 claims 2
• XBZYWSMVVKYHQN-MYPRUECHSA-N (4as,6as,6br,8ar,9r,10s,12ar,12br,14bs)-10-hydroxy-2,2,6a,6b,9,12a-hexamethyl-9-[(sulfooxy)methyl]-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylic acid Chemical compound C1C[C@H](O)[C@@](C)(COS(O)(=O)=O)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C XBZYWSMVVKYHQN-MYPRUECHSA-N 0.000 claims 1
• RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 claims 1
• JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims 1
• IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 claims 1
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
• HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 claims 1
• GDGIXKWOJJMLNP-UHFFFAOYSA-N 2-[2,2-bis(1h-indol-3-yl)ethyl]aniline Chemical compound NC1=CC=CC=C1CC(C=1C2=CC=CC=C2NC=1)C1=CNC2=CC=CC=C12 GDGIXKWOJJMLNP-UHFFFAOYSA-N 0.000 claims 1
• XYYXDARQOHWBPO-UHFFFAOYSA-N 3,5-dimethyl-1h-1,2,4-triazole Chemical compound CC1=NNC(C)=N1 XYYXDARQOHWBPO-UHFFFAOYSA-N 0.000 claims 1
• RNKGDBXXIBUOTR-UHFFFAOYSA-N 3,6-dioxocyclohexa-1,4-diene-1-carbonitrile Chemical compound O=C1C=CC(=O)C(C#N)=C1 RNKGDBXXIBUOTR-UHFFFAOYSA-N 0.000 claims 1
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
• LKJPSUCKSLORMF-UHFFFAOYSA-N Monolinuron Chemical compound CON(C)C(=O)NC1=CC=C(Cl)C=C1 LKJPSUCKSLORMF-UHFFFAOYSA-N 0.000 claims 1
• PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims 1
• 125000005577 anthracene group Chemical group 0.000 claims 1
• 230000000747 cardiac effect Effects 0.000 claims 1
• 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
• XLXAISIGOXCPHN-UHFFFAOYSA-N heptadec-1-en-7-ol Chemical compound CCCCCCCCCCC(O)CCCCC=C XLXAISIGOXCPHN-UHFFFAOYSA-N 0.000 claims 1
• OMQILORXGICXPX-UHFFFAOYSA-N hex-1-en-2-amine Chemical compound CCCCC(N)=C OMQILORXGICXPX-UHFFFAOYSA-N 0.000 claims 1
• 125000005597 hydrazone group Chemical group 0.000 claims 1
• 206010020718 hyperplasia Diseases 0.000 claims 1
• 208000027061 mild cognitive impairment Diseases 0.000 claims 1
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
• JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical group CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 claims 1
• 239000000758 substrate Substances 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 2
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• 239000000203 mixture Substances 0.000 description 265
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• 238000010521 absorption reaction Methods 0.000 description 97
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• 238000002835 absorbance Methods 0.000 description 28
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
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