TW200813035A - Novel heteroaryl substituted benzoxazoles - Google Patents

Info

Publication number

TW200813035A

TW200813035A TW096120843A TW96120843A TW200813035A TW 200813035 A TW200813035 A TW 200813035A TW 096120843 A TW096120843 A TW 096120843A TW 96120843 A TW96120843 A TW 96120843A TW 200813035 A TW200813035 A TW 200813035A

Authority

TW

Taiwan

Prior art keywords

alkyl

fluoroalkyl

group

compound

methoxy

Prior art date

2006-06-19

Links

• Espacenet
• Global Dossier
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• 125000001072 heteroaryl group Chemical group 0.000 title abstract description 17
• 150000000183 1,3-benzoxazoles Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 246
• 238000000034 method Methods 0.000 claims abstract description 75
• 239000000203 mixture Substances 0.000 claims abstract description 35
• 150000003839 salts Chemical class 0.000 claims abstract description 33
• BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical class C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims abstract description 30
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 29
• 208000037259 Amyloid Plaque Diseases 0.000 claims abstract description 23
• 239000003814 drug Substances 0.000 claims abstract description 11
• 125000000217 alkyl group Chemical group 0.000 claims description 348
• 125000003709 fluoroalkyl group Chemical group 0.000 claims description 222
• -1 alkyl hydrazine Chemical compound 0.000 claims description 100
• 125000003545 alkoxy group Chemical group 0.000 claims description 90
• OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 49
• 229910052794 bromium Inorganic materials 0.000 claims description 45
• 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 44
• 239000002585 base Substances 0.000 claims description 43
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 42
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 41
• 229910052731 fluorine Inorganic materials 0.000 claims description 41
• 239000011737 fluorine Chemical group 0.000 claims description 39
• 125000002947 alkylene group Chemical group 0.000 claims description 38
• 239000001257 hydrogen Substances 0.000 claims description 31
• 229910052739 hydrogen Inorganic materials 0.000 claims description 31
• 150000001412 amines Chemical class 0.000 claims description 29
• 125000004429 atom Chemical group 0.000 claims description 28
• 239000002243 precursor Substances 0.000 claims description 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 24
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
• 108090000623 proteins and genes Proteins 0.000 claims description 24
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 22
• 238000002360 preparation method Methods 0.000 claims description 22
• 125000001424 substituent group Chemical group 0.000 claims description 20
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
• 125000001153 fluoro group Chemical group F* 0.000 claims description 18
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
• 229910052740 iodine Inorganic materials 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
• 239000000460 chlorine Substances 0.000 claims description 16
• 229910052799 carbon Inorganic materials 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 239000012453 solvate Substances 0.000 claims description 15
• 125000003277 amino group Chemical group 0.000 claims description 14
• 239000007789 gas Substances 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
• 125000000524 functional group Chemical group 0.000 claims description 13
• 238000011282 treatment Methods 0.000 claims description 13
• 150000002148 esters Chemical class 0.000 claims description 12
• 229910052801 chlorine Inorganic materials 0.000 claims description 11
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 11
• ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 10
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 10
• 229910052736 halogen Inorganic materials 0.000 claims description 10
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
• 150000002367 halogens Chemical group 0.000 claims description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims description 9
• 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
• 239000012458 free base Substances 0.000 claims description 8
• 150000003573 thiols Chemical class 0.000 claims description 8
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 7
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
• 239000011734 sodium Substances 0.000 claims description 6
• 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 5
• KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 5
• KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 5
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
• 229910052707 ruthenium Inorganic materials 0.000 claims description 5
• KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims description 5
• GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 5
• FKYKJYSYSGEDCG-UHFFFAOYSA-N 6-methoxy-1,3-benzoxazole Chemical compound COC1=CC=C2N=COC2=C1 FKYKJYSYSGEDCG-UHFFFAOYSA-N 0.000 claims description 4
• 125000005605 benzo group Chemical group 0.000 claims description 4
• 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
• 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 3
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 125000006612 decyloxy group Chemical group 0.000 claims description 3
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
• 230000009977 dual effect Effects 0.000 claims description 3
• 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 claims description 3
• 208000015756 familial Alzheimer disease Diseases 0.000 claims description 3
• 229960003132 halothane Drugs 0.000 claims description 3
• BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 claims description 3
• 229910052760 oxygen Inorganic materials 0.000 claims description 3
• 239000001301 oxygen Substances 0.000 claims description 3
• 125000000565 sulfonamide group Chemical group 0.000 claims description 3
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 2
• MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 claims description 2
• QMZQYCHTMLIPOK-UHFFFAOYSA-N 5-(6-methoxy-1,3-benzoxazol-2-yl)pyrimidin-2-amine Chemical compound O1C2=CC(OC)=CC=C2N=C1C1=CN=C(N)N=C1 QMZQYCHTMLIPOK-UHFFFAOYSA-N 0.000 claims description 2
• UDAVSWULZNLITD-UHFFFAOYSA-N 5-(6-methyl-1,3-benzoxazol-2-yl)pyrimidin-2-amine Chemical compound O1C2=CC(C)=CC=C2N=C1C1=CN=C(N)N=C1 UDAVSWULZNLITD-UHFFFAOYSA-N 0.000 claims description 2
• 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 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
• IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 claims description 2
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
• NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 2
• JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 2
• SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical compound N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 claims description 2
• 125000006501 nitrophenyl group Chemical group 0.000 claims description 2
• 230000002265 prevention Effects 0.000 claims description 2
• LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 2
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 2
• 229910052708 sodium Inorganic materials 0.000 claims description 2
• 208000011580 syndromic disease Diseases 0.000 claims description 2
• 238000002560 therapeutic procedure Methods 0.000 claims description 2
• SLGBZMMZGDRARJ-UHFFFAOYSA-N triphenylene Chemical compound C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 claims description 2
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
• 229920002554 vinyl polymer Polymers 0.000 claims description 2
• UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims 2
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 2
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 2
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims 2
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
• 125000000714 pyrimidinyl group Chemical group 0.000 claims 2
• 210000003296 saliva Anatomy 0.000 claims 2
• HZONRRHNQILCNO-UHFFFAOYSA-N 1-methyl-2h-pyridine Chemical compound CN1CC=CC=C1 HZONRRHNQILCNO-UHFFFAOYSA-N 0.000 claims 1
• NRBCYYCKOXRXRB-UHFFFAOYSA-N 2-methoxy-1,3-benzoxazole Chemical compound C1=CC=C2OC(OC)=NC2=C1 NRBCYYCKOXRXRB-UHFFFAOYSA-N 0.000 claims 1
• XYVMOLOUBJBNBF-UHFFFAOYSA-N 3h-1,3-oxazol-2-one Chemical compound OC1=NC=CO1 XYVMOLOUBJBNBF-UHFFFAOYSA-N 0.000 claims 1
• 108010060159 Apolipoprotein E4 Proteins 0.000 claims 1
• KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims 1
• 206010052428 Wound Diseases 0.000 claims 1
• 208000027418 Wounds and injury Diseases 0.000 claims 1
• 150000001356 alkyl thiols Chemical class 0.000 claims 1
• FXOFAYKVTOLJTJ-UHFFFAOYSA-N fluoridooxygen(.) Chemical compound F[O] FXOFAYKVTOLJTJ-UHFFFAOYSA-N 0.000 claims 1
• 235000019253 formic acid Nutrition 0.000 claims 1
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims 1
• BQIGMBPWIKZNQY-UHFFFAOYSA-N n-aminothiohydroxylamine Chemical group NNS BQIGMBPWIKZNQY-UHFFFAOYSA-N 0.000 claims 1
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
• VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 claims 1
• DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 1
• 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
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• 238000006243 chemical reaction Methods 0.000 description 33
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
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• 125000003118 aryl group Chemical group 0.000 description 16
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• 125000000623 heterocyclic group Chemical group 0.000 description 13
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• 150000002431 hydrogen Chemical group 0.000 description 9
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• 229910052763 palladium Inorganic materials 0.000 description 6
• 239000012312 sodium hydride Substances 0.000 description 6
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• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 5
• 125000005842 heteroatom Chemical group 0.000 description 5
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
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