JPWO2007148755A1 - 新規アミロイド親和性化合物 - Google Patents
新規アミロイド親和性化合物 Download PDFInfo
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- JPWO2007148755A1 JPWO2007148755A1 JP2008522509A JP2008522509A JPWO2007148755A1 JP WO2007148755 A1 JPWO2007148755 A1 JP WO2007148755A1 JP 2008522509 A JP2008522509 A JP 2008522509A JP 2008522509 A JP2008522509 A JP 2008522509A JP WO2007148755 A1 JPWO2007148755 A1 JP WO2007148755A1
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- Prior art keywords
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- mmol
- compound
- pyridine
- substituent
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 103
- 230000002285 radioactive effect Effects 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 16
- 150000002367 halogens Chemical group 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 239000000032 diagnostic agent Substances 0.000 claims abstract description 9
- 229940039227 diagnostic agent Drugs 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000003277 amino group Chemical group 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 231100000053 low toxicity Toxicity 0.000 claims abstract description 6
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 4
- 238000000034 method Methods 0.000 claims description 15
- 208000024827 Alzheimer disease Diseases 0.000 claims description 13
- 238000003384 imaging method Methods 0.000 claims description 12
- 208000037259 Amyloid Plaque Diseases 0.000 claims description 10
- 238000011503 in vivo imaging Methods 0.000 claims description 5
- 230000003941 amyloidogenesis Effects 0.000 claims description 4
- 238000001727 in vivo Methods 0.000 claims description 3
- 238000002603 single-photon emission computed tomography Methods 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical group OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 201000010099 disease Diseases 0.000 abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 9
- 230000007886 mutagenicity Effects 0.000 abstract description 9
- 231100000299 mutagenicity Toxicity 0.000 abstract description 9
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 118
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- 239000000243 solution Substances 0.000 description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- 238000006243 chemical reaction Methods 0.000 description 76
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- 239000000203 mixture Substances 0.000 description 43
- 230000002829 reductive effect Effects 0.000 description 43
- 239000000047 product Substances 0.000 description 38
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- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 32
- 239000002244 precipitate Substances 0.000 description 32
- 238000004128 high performance liquid chromatography Methods 0.000 description 31
- 210000004556 brain Anatomy 0.000 description 30
- 239000002904 solvent Substances 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 238000003786 synthesis reaction Methods 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- 238000010992 reflux Methods 0.000 description 23
- 239000003480 eluent Substances 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- LJYOFQHKEWTQRH-UHFFFAOYSA-N 2-bromo-1-(4-hydroxyphenyl)ethanone Chemical compound OC1=CC=C(C(=O)CBr)C=C1 LJYOFQHKEWTQRH-UHFFFAOYSA-N 0.000 description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 17
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 16
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- 239000000523 sample Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 238000011156 evaluation Methods 0.000 description 14
- 239000011259 mixed solution Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- XJKJHILCYUUVSJ-UHFFFAOYSA-N 5-methoxypyridin-2-amine Chemical compound COC1=CC=C(N)N=C1 XJKJHILCYUUVSJ-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- QJBHTNVCHGXHAB-UHFFFAOYSA-N 6-iodo-2-phenylimidazo[1,2-a]pyridine Chemical compound C=1N2C=C(I)C=CC2=NC=1C1=CC=CC=C1 QJBHTNVCHGXHAB-UHFFFAOYSA-N 0.000 description 10
- ZHWJONXIBRILIF-UHFFFAOYSA-N 4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenol Chemical compound C=1N2C=C(OC)C=CC2=NC=1C1=CC=C(O)C=C1 ZHWJONXIBRILIF-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004364 calculation method Methods 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- YBOCOHMLQZAQQZ-UHFFFAOYSA-N 4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(I)C=C2)C2=N1 YBOCOHMLQZAQQZ-UHFFFAOYSA-N 0.000 description 8
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000009825 accumulation Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- ZKEAOLVGPKCNCT-UHFFFAOYSA-N 2-bromo-3-methoxy-6-nitropyridine Chemical compound COC1=CC=C([N+]([O-])=O)N=C1Br ZKEAOLVGPKCNCT-UHFFFAOYSA-N 0.000 description 7
- PDOWLYNSFYZIQX-UHFFFAOYSA-N 2-bromo-3-methoxypyridine Chemical compound COC1=CC=CN=C1Br PDOWLYNSFYZIQX-UHFFFAOYSA-N 0.000 description 7
- 230000008499 blood brain barrier function Effects 0.000 description 7
- KPMVHELZNRNSMN-UHFFFAOYSA-N chembl1985849 Chemical compound N1=CC=C2NCCN21 KPMVHELZNRNSMN-UHFFFAOYSA-N 0.000 description 7
- 238000003745 diagnosis Methods 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- KRHYYFGTRYWZRS-BJUDXGSMSA-M fluorine-18(1-) Chemical compound [18F-] KRHYYFGTRYWZRS-BJUDXGSMSA-M 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- 239000012488 sample solution Substances 0.000 description 7
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- HQVATKNWZYCFHS-UHFFFAOYSA-N 3-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenoxy]propyl 4-methylbenzenesulfonate Chemical compound C=1N2C=C(OC)C=CC2=NC=1C(C=C1)=CC=C1OCCCOS(=O)(=O)C1=CC=C(C)C=C1 HQVATKNWZYCFHS-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- VNHWPVLQRKKKRY-UHFFFAOYSA-N 1-bromo-3-fluoropropane Chemical compound FCCCBr VNHWPVLQRKKKRY-UHFFFAOYSA-N 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 238000009206 nuclear medicine Methods 0.000 description 5
- 239000003444 phase transfer catalyst Substances 0.000 description 5
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- BCQLNMVTXCZBFR-UHFFFAOYSA-N 2-[4-(3-fluoropropoxy)phenyl]imidazo[1,2-a]pyridine Chemical compound C1=CC(OCCCF)=CC=C1C1=CN(C=CC=C2)C2=N1 BCQLNMVTXCZBFR-UHFFFAOYSA-N 0.000 description 4
- YKHQFTANTNMYPP-UHFFFAOYSA-N 2-bromopyridin-3-ol Chemical compound OC1=CC=CN=C1Br YKHQFTANTNMYPP-UHFFFAOYSA-N 0.000 description 4
- DJAPVDCXTHRTAM-UHFFFAOYSA-N 4-(6-bromoimidazo[1,2-a]pyridin-2-yl)phenol Chemical compound C1=CC(O)=CC=C1C1=CN(C=C(Br)C=C2)C2=N1 DJAPVDCXTHRTAM-UHFFFAOYSA-N 0.000 description 4
- ZWIARAQZLULYPG-NSCUHMNNSA-N 4-[(e)-2-[4-(methylamino)phenyl]ethenyl]phenol Chemical compound C1=CC(NC)=CC=C1\C=C\C1=CC=C(O)C=C1 ZWIARAQZLULYPG-NSCUHMNNSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 4
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- -1 [18 F] fluoride ions Chemical class 0.000 description 4
- 206010002022 amyloidosis Diseases 0.000 description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- 239000002243 precursor Substances 0.000 description 4
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- IAVCEBMLYVGBLA-UHFFFAOYSA-N 2-[1-[6-[2-fluoroethyl(methyl)amino]naphthalen-2-yl]ethylidene]propanedinitrile Chemical compound C1=C(C(C)=C(C#N)C#N)C=CC2=CC(N(CCF)C)=CC=C21 IAVCEBMLYVGBLA-UHFFFAOYSA-N 0.000 description 3
- YDMVHZJFEJLHGF-SQZVAGKESA-N 2-[4-(3-fluoranylpropoxy)phenyl]-6-methoxyimidazo[1,2-a]pyridine Chemical compound C=1N2C=C(OC)C=CC2=NC=1C1=CC=C(OCCC[18F])C=C1 YDMVHZJFEJLHGF-SQZVAGKESA-N 0.000 description 3
- YDMVHZJFEJLHGF-UHFFFAOYSA-N 2-[4-(3-fluoropropoxy)phenyl]-6-methoxyimidazo[1,2-a]pyridine Chemical compound C=1N2C=C(OC)C=CC2=NC=1C1=CC=C(OCCCF)C=C1 YDMVHZJFEJLHGF-UHFFFAOYSA-N 0.000 description 3
- GMWFPSPTDMITFZ-UHFFFAOYSA-N 3-hydroxypropyl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCCCO)C=C1 GMWFPSPTDMITFZ-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-AHCXROLUSA-N Iodine-123 Chemical compound [123I] ZCYVEMRRCGMTRW-AHCXROLUSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000003920 cognitive function Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
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- 238000012636 positron electron tomography Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 238000005185 salting out Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 3
- DKFFAVRVYDPJBA-UHFFFAOYSA-N tributyl-[2-[4-(3-fluoropropoxy)phenyl]imidazo[1,2-a]pyridin-6-yl]stannane Chemical compound C=1N2C=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=1C1=CC=C(OCCCF)C=C1 DKFFAVRVYDPJBA-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
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Images
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
このような脳内アミロイド画像診断用プローブの多くは、アミロイドに対する親和性が高く、かつ脳移行性の高い疎水性の低分子化合物を、種々の放射性核種、例えば11C、18F及び123I等で標識した化合物である。具体例として、6−ヨード−2−[4’−(N,N−ジメチルアミノ)フェニル]ベンゾチアゾール(以下、TZDMという)や6−ヒドロキシ−2−[4’−(N−メチルアミノ)フェニル]ベンゾチアゾール(以下、6−OH−BTA−1という)を始めとする種々のチオフラビン誘導体(特許文献1、非特許文献3)、(E)−4−メチルアミノ−4’―ヒドロキシスチルベン(以下、SB−13という)や(E)−4−ジメチルアミノ−4’―ヨードスチルベン(以下、m−I−SBという)を初めとするスチルベン化合物(特許文献2、非特許文献4,非特許文献5)、6−ヨード−2−[4’−(N,N−ジメチルアミノ)フェニル]ベンゾオキサゾール(以下、IBOXという)、6−[2−(フルオロ)エトキシ]−2−[2−(2−ジメチルアミノチアゾール−5−イル)エテニル]ベンゾオキサゾールを初めとするベンゾオキサゾール誘導体(非特許文献6,非特許文献7)、2−(1−{6−[(2−フルオロエチル)(メチル)アミノ]−2−ナフチル}エチリデン)マロノニトリル(以下、FDDNPという)を初めとするDDNP誘導体(特許文献4、非特許文献8)及び6−ヨード−2−[4’−(N,N−ジメチルアミノ)フェニル]イミダゾ[1,2−a]ピリジン(以下、IMPYという)を初めとするイミダゾピリジン誘導体(特許文献3、非特許文献9)等を11Cや放射性ハロゲンで標識した化合物が報告されている。さらに、これらの画像診断用プローブの一部については、ヒトイメージング研究が実施され、AD患者において健常例とは明らかに異なる脳への放射能集積を示すことが報告されている(非特許文献10、非特許文献11)。
TZDM、IBOX及びm−I−SBのヨードを[125I]で標識した化合物は、正常マウスを用いた実験の結果、投与後2分点において、いずれも脳内への移行が認められている。しかしこれらの化合物は、正常組織からのクリアランスが十分ではなく、投与後の時間経過に伴い、徐々に脳内に集積する傾向を示している(特表2005−512945号公報、Zhi-Ping Zhuang et al.,Nuclear Medicine and Biology, 2001, 28, p.887-894、H. F. Kung et al.,J. Am. Chem. Soc., 2001, 123, p.12740-12741)。正常組織からのクリアランスが十分でないと、アミロイド集積部位において十分なコントラストが得られないといった問題がある。SB−13を[11C]で標識した化合物については、ラットを用いた実験より正常組織からのクリアランスを有することが示されているが、そのクリアランス速度は十分に速いとはいえない(Masahiro Ono et al., Nuclear Medicine and Biology, 2003, 30, p.565-571)。
FDDNPについても、復帰突然変異試験にて陽性を示すことが、報告されている。(国際公開第03/106439号パンフレット)
R2は、任意の放射性ハロゲン置換基を用いることができ、18F、76Br、123I、124I、125I又は131Iより選択されるハロゲンを用いることが好ましく、18F、76Br、123I又は125Iより選択されるハロゲンを用いることがより好ましく、18Fであることが特に好ましい。
また、mは0〜2の整数である。
本発明のさらに他の側面によれば、医薬用途に使用される、前記式(1)で表される化合物またはその塩が提供される。
本発明のさらに他の側面によれば、アミロイド沈着のインビボ撮像用途に使用される前記式(1)で表される化合物またはその塩が提供される。
本発明のさらに他の側面によれば、(a)前記式(1)で表される化合物またはその塩の検出可能な量を投与するステップと、
(b)前記化合物またはその塩の患者のアミロイド沈着への結合を検出するステップと、
を含んでなる、患者のアミロイド沈着をインビボで検出する方法が提供される。
本発明の好ましい実施形態によれば、前記ステップ(b)は、PET又はSPECT撮像により行われる。
非放射性ハロゲン置換基としては、放射性フッ素を用いた求核置換反応における標的となりうるハロゲンを用いることができ、好ましくはヨウ素又は臭素を用いることができる。
また、mは0〜2の整数である。
なお、下記実施例において、各化合物の名称を、表1のように定義した。
1H−NMR(溶媒:重クロロホルム、共鳴周波数:500MHz):δ 7.83-7.79 ( m, 2H ), 7.64-7.63 ( s, 1H ), 7.56-7.54 ( m, 1H ), 7.48-7.45 ( m, 1H ), 6.95-6.92 ( m, 2H ), 6.93-6.90 ( m, 1H ), 4.65 ( dt, 2JHF = 47.0 Hz, J = 6.0 Hz, 2H ), 4.11 ( t, J = 6.0 Hz, 2H ), 3.75 ( s, 3H ), 2.17 ( dquint, 3JHF = 25.9 Hz, J = 6.0 Hz, 2H )。
1H−NMR(溶媒:重ジメチルスルホキシド、共鳴周波数:270MHz):δ 8.52 ( s, 2H ), 8.30-8.25 ( m, 1H ), 7.85-7.79 ( m, 1H ), 7.67-7.62 ( m, 1H ), 7.22-7.16 ( m, 2H ), 5.64 ( s, 1H ), 4.62 ( dt, 2JHF = 47.0 Hz, J = 5.9 Hz, 2H ), 4.17 ( t, J = 5.9 Hz, 2H ), 2.14 ( dquint, 3JHF = 26.2 Hz, J = 5.9 Hz, 2H )。
1H−NMR(溶媒:重クロロホルム、共鳴周波数:500MHz):δ 8.09 ( dt, J = 6.9, 1.2 Hz, 1H ), 7.90-7.86 ( m, 2H ), 7.76 ( d, J = 0.7 Hz, 1H ), 7.62-7.59 ( m, 1H ), 7.14 ( ddd, J = 9.1, 6.7, 1.2 Hz, 1H ), 6.99-6.95 ( m, 2H ), 6.75 ( dt, J = 6.7, 1.2 Hz, 1H ), 4.67 ( dt, 2JHF = 47.0 Hz, J = 6.0 Hz, 2H ), 4.14 ( t, J = 6.0 Hz, 2H ), 2.19 ( dquint., 3JHF = 25.9 Hz, J = 6.0 Hz, 2H )。
1H−NMR(溶媒:重クロロホルム、共鳴周波数:500MHz):δ8.37-8.35 ( m, 1H ), 7.88-7.84 ( m, 2H ), 7.72 ( s, 1H ), 7.42-7.39 ( m, 1H ), 7.32 ( dd, J = 9.4, 1.6 Hz, 1H ), 6.99-6.96 ( m, 2H ), 4.67 ( dt, 2JHF = 47.0 Hz, J = 6.0 Hz, 2H ), 4.15 ( t, J = 6.0 Hz, 2H ), 2.20 ( dquint, 3JHF = 25.9 Hz, J = 6.0 Hz, 2H )。
1H−NMR(溶媒:重ジメチルスルホキシド、共鳴周波数:500MHz):δ8.86-8.84 ( m, 1H ), 8.14 ( s, 1H ), 7.78-7.74 ( m, 2H ), 7.40-7.35 ( m, 2H ), 6.86-6.82 ( m, 2H )。
1H−NMR(溶媒:重クロロホルム、共鳴周波数:500MHz):δ8.01-7.93 ( m, 1H ), 7.91-7.87 ( m, 2H ), 7.75-7.74 ( m, 1H ), 7.63-7.58 ( m, 1H ), 7.20-7.11 ( m, 1H ), 7.00-6.95 ( m, 2H ), 4.67 ( dt, JHF = 47.0 Hz, J = 6.0 Hz, 2H ), 4.15 ( t, J = 6.0 Hz, 2H ), 2.20 ( dquint, JHF = 26.1 Hz, J = 6.0 Hz, 2H ), 1.64-1.47 ( m, 6H ), 1.39-1.31 ( m, 6H ), 1.19-1.04 ( m, 6H ), 0.91 ( t, J = 7.2 Hz, 9H )
カラム:Phenomenex Luna C18(商品名、Phenomenex社製、サイズ:4.6×150mm)
移動相:0.1%トリフルオロ酢酸/0.1%トリフルオロ酢酸を含むアセトニトリル=80/20→0/100(17分)
流速:1.0 mL/分
検出器:紫外可視吸光光度計(検出波長:282nm)及び放射線検出器 (raytest社 STEFFI型)
TLCプレート:RP−18F254(製品名、メルク社製)
展開相:メタノール/水=20/1
検出器:バイオイメージングアナライザー,BAS−2500(形式:BAS−2500、富士写真フィルム株式会社製)
1H−NMR(溶媒:重クロロホルム、共鳴周波数:500MHz):δ7.81-7.77 ( m, 2H ), 7.76-7.72 ( m, 2H ), 7.71-7.70 ( m, 1H ), 7.64-7.62 ( m, 1H ), 7.49-7.46 ( m, 2H ), 7.24-7.21 ( m, 2H ), 6.95-6.92 ( m, 1H ), 6.81-6.77 ( m, 2H ), 4.25 ( t, J = 6.0 Hz, 2H ), 3.95 ( t, J = 6.0 Hz, 2H ), 3.80 ( s, 3H ), 2.34 ( s, 3H ), 2.11 ( quint., J = 6.0 Hz, 2H )。
TLCプレート:Silica Gel 60 F254(製品名、メルク社製)
展開相:クロロホルム/メタノール/トリエチルアミン=50/1/2
検出器:Rita Star(製品名、raytest社製)
本発明化合物のアミロイド親和性を、以下のin vitro結合試験により評価した。
カラム:Prodigy ODS(3)(製品名、phenomenex社製、サイズ:4.6×250 mm)
移動相:50mMトリエチルアミンリン酸(pH 7.2)/アセトニトリル=40/60混液
流速:0.7mL/分
検出器:紫外可視吸光光度計(検出波長:282nm)
この結果より、化合物4は、脳内アミロイドに集積する性能を有し、脳内アミロイドの描出能を有することが示唆された。
Claims (12)
- R2が、18F、76Br、123I、124I、125I又は131Iからなる群より選択される、請求項1記載の化合物またはその塩。
- R2が、18Fである、請求項1または2記載の化合物またはその塩。
- R2が、18F、76Br、123I、124I、125I又は131Iからなる群より選択される、請求項5記載の低毒性アルツハイマー病診断剤。
- R2が、18Fである、請求項5又は6記載の低毒性アルツハイマー病診断剤。
- 請求項1乃至3の何れか1項に記載の式(1)で表される化合物またはその塩と、薬学的に許容される担体または賦形剤とを含んでなる、アミロイド沈着のインビボ撮像用医薬組成物。
- 医薬用途に使用される、請求項1乃至3の何れか1項に記載の式(1)で表される化合物またはその塩。
- アミロイド沈着のインビボ撮像用途に使用される請求項1乃至3の何れか1項に記載の式(1)で表される化合物またはその塩。
- (a)請求項1乃至3の何れか1項に記載の式(1)で表される化合物またはその塩の検出可能な量を投与するステップと、
(b)前記化合物またはその塩の患者のアミロイド沈着への結合を検出するステップと、
を含んでなる、患者のアミロイド沈着をインビボで検出する方法。 - 前記ステップ(b)はPET又はSPECT撮像により行われる、請求項11に記載の方法。
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