JP5417578B2 - 心筋灌流イメージングのための造影剤 - Google Patents
心筋灌流イメージングのための造影剤 Download PDFInfo
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- JP5417578B2 JP5417578B2 JP2006553329A JP2006553329A JP5417578B2 JP 5417578 B2 JP5417578 B2 JP 5417578B2 JP 2006553329 A JP2006553329 A JP 2006553329A JP 2006553329 A JP2006553329 A JP 2006553329A JP 5417578 B2 JP5417578 B2 JP 5417578B2
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- ethyl acetate
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- 238000003384 imaging method Methods 0.000 title claims description 108
- 230000002107 myocardial effect Effects 0.000 title claims description 9
- 230000010412 perfusion Effects 0.000 title claims description 6
- 239000002872 contrast media Substances 0.000 title description 43
- 229940039231 contrast media Drugs 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims description 123
- 150000001875 compounds Chemical class 0.000 claims description 73
- 238000004519 manufacturing process Methods 0.000 claims description 62
- 239000003814 drug Substances 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 416
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 319
- 239000000243 solution Substances 0.000 description 223
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 199
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 182
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 153
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 152
- 235000019439 ethyl acetate Nutrition 0.000 description 139
- 239000000203 mixture Substances 0.000 description 139
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 102
- 239000000047 product Substances 0.000 description 100
- 238000006243 chemical reaction Methods 0.000 description 96
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 91
- 239000000741 silica gel Substances 0.000 description 89
- 229910002027 silica gel Inorganic materials 0.000 description 89
- -1 MPP + Chemical compound 0.000 description 83
- 239000011541 reaction mixture Substances 0.000 description 81
- 239000012044 organic layer Substances 0.000 description 64
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 62
- 239000003921 oil Substances 0.000 description 62
- 238000003818 flash chromatography Methods 0.000 description 54
- 239000011734 sodium Substances 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 45
- 125000003118 aryl group Chemical group 0.000 description 42
- 229910052739 hydrogen Inorganic materials 0.000 description 39
- 239000001257 hydrogen Substances 0.000 description 39
- 239000013058 crude material Substances 0.000 description 37
- 229910052757 nitrogen Inorganic materials 0.000 description 37
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 36
- 150000002431 hydrogen Chemical group 0.000 description 35
- 239000002904 solvent Substances 0.000 description 35
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 33
- 239000010410 layer Substances 0.000 description 32
- 239000003446 ligand Substances 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 238000000746 purification Methods 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 27
- 239000007864 aqueous solution Substances 0.000 description 26
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 26
- DWFZBUWUXWZWKD-UHFFFAOYSA-N pyridaben Chemical compound C1=CC(C(C)(C)C)=CC=C1CSC1=C(Cl)C(=O)N(C(C)(C)C)N=C1 DWFZBUWUXWZWKD-UHFFFAOYSA-N 0.000 description 26
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 150000002084 enol ethers Chemical class 0.000 description 25
- 125000001072 heteroaryl group Chemical group 0.000 description 25
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000001816 cooling Methods 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 24
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 23
- 229910000077 silane Inorganic materials 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000003480 eluent Substances 0.000 description 21
- 229910052760 oxygen Inorganic materials 0.000 description 21
- 125000000217 alkyl group Chemical group 0.000 description 20
- 239000012267 brine Substances 0.000 description 20
- 229910052799 carbon Inorganic materials 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 239000002253 acid Substances 0.000 description 19
- ORDAZKGHSNRHTD-UHFFFAOYSA-N alpha-Toxicarol Natural products O1C(C)(C)C=CC2=C1C=CC1=C2OC2COC(C=C(C(=C3)OC)OC)=C3C2C1=O ORDAZKGHSNRHTD-UHFFFAOYSA-N 0.000 description 19
- 125000004429 atom Chemical group 0.000 description 19
- 239000012043 crude product Substances 0.000 description 19
- 229920006395 saturated elastomer Polymers 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 125000003545 alkoxy group Chemical group 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- 125000000623 heterocyclic group Chemical group 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- ZZYSLNWGKKDOML-UHFFFAOYSA-N tebufenpyrad Chemical compound CCC1=NN(C)C(C(=O)NCC=2C=CC(=CC=2)C(C)(C)C)=C1Cl ZZYSLNWGKKDOML-UHFFFAOYSA-N 0.000 description 17
- GSZRULWGAWHHRI-UHFFFAOYSA-N deguelin Natural products O1C=CC(C)(C)C2=C1C=CC1=C2OC2COC(C=C(C(=C3)OC)OC)=C3C2C1=O GSZRULWGAWHHRI-UHFFFAOYSA-N 0.000 description 16
- 238000001704 evaporation Methods 0.000 description 16
- 230000008020 evaporation Effects 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 16
- 239000012217 radiopharmaceutical Substances 0.000 description 16
- 229940121896 radiopharmaceutical Drugs 0.000 description 16
- 230000002799 radiopharmaceutical effect Effects 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 239000000523 sample Substances 0.000 description 15
- 239000003643 water by type Substances 0.000 description 15
- 0 CC(*)(*)C(*)(*)c1n[n](C)c(C)c1* Chemical compound CC(*)(*)C(*)(*)c1n[n](C)c(C)c1* 0.000 description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 14
- 239000001301 oxygen Substances 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 239000012141 concentrate Substances 0.000 description 13
- 239000012299 nitrogen atmosphere Substances 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- 239000002738 chelating agent Substances 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 239000007789 gas Substances 0.000 description 12
- 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 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 239000005663 Pyridaben Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 208000007536 Thrombosis Diseases 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- ORDAZKGHSNRHTD-UXHICEINSA-N deguelin Chemical compound O1C(C)(C)C=CC2=C1C=CC1=C2O[C@@H]2COC(C=C(C(=C3)OC)OC)=C3[C@@H]2C1=O ORDAZKGHSNRHTD-UXHICEINSA-N 0.000 description 10
- 238000010828 elution Methods 0.000 description 10
- 150000002632 lipids Chemical class 0.000 description 10
- 229910052751 metal Inorganic materials 0.000 description 10
- 239000002184 metal Substances 0.000 description 10
- 239000011698 potassium fluoride Substances 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
- 239000010779 crude oil Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- 239000012280 lithium aluminium hydride Substances 0.000 description 9
- 229910021645 metal ion Inorganic materials 0.000 description 9
- 230000005298 paramagnetic effect Effects 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- MUQMCEBEBSCGLB-UHFFFAOYSA-N 4-(4-methylphenyl)butan-1-ol Chemical compound CC1=CC=C(CCCCO)C=C1 MUQMCEBEBSCGLB-UHFFFAOYSA-N 0.000 description 8
- 238000009007 Diagnostic Kit Methods 0.000 description 8
- 239000005658 Tebufenpyrad Substances 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000004005 microsphere Substances 0.000 description 8
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- 235000003270 potassium fluoride Nutrition 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
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- 239000000725 suspension Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 229910052805 deuterium Inorganic materials 0.000 description 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 7
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 7
- HYHVRDPIPYBIRC-UHFFFAOYSA-N 2-tert-butyl-4-chloro-5-hydroxypyridazin-3-one Chemical compound CC(C)(C)N1N=CC(O)=C(Cl)C1=O HYHVRDPIPYBIRC-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- QVDYYQXUNAQSNI-UHFFFAOYSA-N ethyl acetate;pentane Chemical compound CCCCC.CCOC(C)=O QVDYYQXUNAQSNI-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 125000004043 oxo group Chemical group O=* 0.000 description 6
- 238000012746 preparative thin layer chromatography Methods 0.000 description 6
- 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 6
- 125000001424 substituent group Chemical group 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- ANFVZRTXGLHTNI-UHFFFAOYSA-N 2-tert-butyl-4,5-dichloropyridazin-3-one Chemical compound CC(C)(C)N1N=CC(Cl)=C(Cl)C1=O ANFVZRTXGLHTNI-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 239000002616 MRI contrast agent Substances 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229910000365 copper sulfate Inorganic materials 0.000 description 5
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 210000003470 mitochondria Anatomy 0.000 description 5
- 238000009206 nuclear medicine Methods 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- NJDRJGINBGXDOI-UHFFFAOYSA-N 1-(4-tert-butylphenyl)-2-quinazolin-4-yloxyethanol Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)COC1=NC=NC2=CC=CC=C12 NJDRJGINBGXDOI-UHFFFAOYSA-N 0.000 description 4
- NNPXCFIPWDBGNX-UHFFFAOYSA-N 1-(4-tert-butylphenyl)ethane-1,2-diol Chemical compound CC(C)(C)C1=CC=C(C(O)CO)C=C1 NNPXCFIPWDBGNX-UHFFFAOYSA-N 0.000 description 4
- MWDICCJVJOMHSI-UHFFFAOYSA-N 2,4-dihydroxy-5-nitrobenzaldehyde Chemical compound OC1=CC(O)=C([N+]([O-])=O)C=C1C=O MWDICCJVJOMHSI-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- WKIVVJQLVZMPNY-UHFFFAOYSA-N 2-[tert-butyl(dimethyl)silyl]oxy-1-(4-tert-butylphenyl)ethanol Chemical compound CC(C)(C)C1=CC=C(C(O)CO[Si](C)(C)C(C)(C)C)C=C1 WKIVVJQLVZMPNY-UHFFFAOYSA-N 0.000 description 4
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 4
- 125000004011 3 membered carbocyclic group Chemical group 0.000 description 4
- 125000001845 4 membered carbocyclic group Chemical group 0.000 description 4
- IXWOVMRDYFFXGI-UHFFFAOYSA-N 4-(4-methylphenyl)butanoic acid Chemical compound CC1=CC=C(CCCC(O)=O)C=C1 IXWOVMRDYFFXGI-UHFFFAOYSA-N 0.000 description 4
- IMERWDVCUKCXJQ-UHFFFAOYSA-N 4-[4-(bromomethyl)phenyl]butoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCCCC1=CC=C(CBr)C=C1 IMERWDVCUKCXJQ-UHFFFAOYSA-N 0.000 description 4
- LYVZIARJWLMUFS-UHFFFAOYSA-N 4-but-2-ynoxy-1,2-dimethoxybenzene Chemical compound COC1=CC=C(OCC#CC)C=C1OC LYVZIARJWLMUFS-UHFFFAOYSA-N 0.000 description 4
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical compound C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-UHFFFAOYSA-N 0.000 description 4
- JUEJBYZTEQNQTK-UHFFFAOYSA-N 4-tert-butyl-3-nitrobenzamide Chemical compound CC(C)(C)C1=CC=C(C(N)=O)C=C1[N+]([O-])=O JUEJBYZTEQNQTK-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- HGAZMNJKRQFZKS-UHFFFAOYSA-N chloroethene;ethenyl acetate Chemical compound ClC=C.CC(=O)OC=C HGAZMNJKRQFZKS-UHFFFAOYSA-N 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
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- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229940005657 pyrophosphoric acid Drugs 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 1
- 229940080817 rotenone Drugs 0.000 description 1
- JUVIOZPCNVVQFO-UHFFFAOYSA-N rotenone Natural products O1C2=C3CC(C(C)=C)OC3=CC=C2C(=O)C2C1COC1=C2C=C(OC)C(OC)=C1 JUVIOZPCNVVQFO-UHFFFAOYSA-N 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- SCPYDCQAZCOKTP-UHFFFAOYSA-N silanol Chemical compound [SiH3]O SCPYDCQAZCOKTP-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229910052714 tellurium Inorganic materials 0.000 description 1
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- DDPWVABNMBRBFI-UHFFFAOYSA-N tert-butylhydrazine;hydron;chloride Chemical compound Cl.CC(C)(C)NN DDPWVABNMBRBFI-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- YUOWTJMRMWQJDA-UHFFFAOYSA-J tin(iv) fluoride Chemical compound [F-].[F-].[F-].[F-].[Sn+4] YUOWTJMRMWQJDA-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- MYAJTCUQMQREFZ-UHFFFAOYSA-K tppts Chemical compound [Na+].[Na+].[Na+].[O-]S(=O)(=O)C1=CC=CC(P(C=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=C(C=CC=2)S([O-])(=O)=O)=C1 MYAJTCUQMQREFZ-UHFFFAOYSA-K 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
- C07D237/16—Two oxygen atoms
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- A61K49/0052—Small organic molecules
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K51/04—Organic compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/0412—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K51/04—Organic compounds
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- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
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Description
本発明は、イメージング分子を含有する新規な化合物、および患者におけるある疾患を診断するためのその使用に関する。
ミトコンドリアは、ほとんどの真核細胞のサイトゾルにわたって分布する膜に囲まれた細胞小器官である。ミトコンドリアは、心筋組織中に特に集中している。
各Aは独立して、O、CHR1、S、またはNR1から選ばれ;
Bは、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれ;
Cは、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、イメージング分子、またはBとの結合から選ばれ;
Dは、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれて;
Eは、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれるか;
EおよびDはそれらが結合する炭素原子と一緒になって二重結合を形成するか;あるいは、
EおよびDはそれらが結合する炭素原子と一緒になってシクロプロピル環を形成し;
R1、R2、R3、R4、R9、R10、R13、およびR14は各々独立して、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれ;
R5およびR6は各々独立して、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、ハロ、ヒドロキシ、またはイメージング分子から選ばれるか;
存在する場合には、R7およびR8は独立して、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、ハロ、ヒドロキシ、またはイメージング分子から選ばれるか;
R5およびR7は一緒になってオキソ基を形成するか;
R6およびR8は一緒になってオキソ基を形成するか;
R7はOであり、そしてR8はR7との結合であり;
但し、
R11は、水素またはヒドロキシであり;
R12は、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれ;
R11およびR12は一緒になって、オキソ基または=CHR1を形成し;
但し、少なくとも1つのイメージング分子は式(I)中に存在する]である。
AはOであり;
BおよびCは各々独立して、CH3またはCH2 18Fであり;
DおよびEは各々独立して、CH3またはCH2 18Fであり;
R5、R6、R9、およびR10は各々独立して、水素または18Fであり;そして、
R11およびR12は一緒になって、オキソ基を形成する。
Gは、
mは0または1であり;
R27、R30、R31、R32、R33、およびR34は独立して、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれ;
存在する場合には、R28は、水素、または場合によりイメージング分子で置換されたC1〜C6アルキルから選ばれ、但し、
存在する場合には、R29は、場合によりイメージング分子で置換されたC1〜C6アルキルであり、但し、
Pは、
存在する場合には、P’は水素であるか;あるいは、
PおよびP’は一緒になってオキソ基を形成し;
但し、
Qは、ハロまたはハロアルキルであり;
Jは、N(R27)、S、O、C(=O)、C(=O)O、NHCH2CH2O、結合、または、C(=O)N(R27)から選ばれ、ここで、各基は、その左端がGと結合し、そしてその右端がR21およびR22で置換された炭素と結合し;
存在する場合には、Kは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれ;
存在する場合には、Lは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれ;
Mは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれるか;あるいは、
LおよびMはそれらが結合する原子と一緒になって、3または4−員の炭素環を形成し;
nは、0、1、2、または3であり;
R21、R22、R23、R24、R25、およびR26は独立して、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれ;そして、
Yは、結合、炭素、または酸素から選ばれ;但し、Yが結合である場合には、KおよびLは存在せず、そしてMは、アリールまたはヘテロアリールから選ばれ;そして、Yが酸素である場合には、KおよびLは存在せず、そしてMは、水素、アルコキシアルキル、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、またはヘテロアリールから選ばれ;
但し、少なくとも1つのイメージング分子は式(II)中に存在する]
である。
Jは、N(R27)、S、O、C(=O)、C(=O)O、NHCH2CH2O、結合、またはC(=O)N(R27)から選ばれ、ここで、各基は、その左端がGと結合し、そしてその右端がR21およびR22で置換された炭素と結合し;
存在する場合には、Kは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれ;
存在する場合には、Lは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれ;
Mは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれるか;あるいは、
LおよびMはそれらが結合する原子と一緒になって、3−または4−員の炭素環を形成し;
Qは、ハロまたはハロアルキルであり;
nは、0、1、2または3であり;
R21、R22、R23、R24、R25、R26、およびR27は独立して、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれ;
R29は、場合によりイメージング分子で置換されたC1〜C6アルキルであり;そして、
Yは、結合、炭素、または酸素から選ばれ;但し、Yが結合である場合には、KおよびLは存在せず、そしてMは、アリールまたはヘテロアリールから選ばれ;そして、Yが酸素である場合には、KおよびLは存在せず、そしてMは、水素、アルコキシアルキル、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、またはヘテロアリールから選ばれ;
但し、少なくとも1つのイメージング分子は式(III)中に存在する]
である。
Jは、N(R27)、S、O、C(=O)、C(=O)O、NHCH2CH2O、結合、またはC(=O)N(R27)から選ばれ、ここで、ここで、各基は、その左端がGと結合し、そしてその右端はR21およびR22で置換された炭素と結合し;
存在する場合には、Kは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれ;
Lは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれ;
Mは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれるか;あるいは、
LおよびMはそれらが結合する原子と一緒になって、3−または4−員の炭素環を形成し;
Qは、ハロまたはハロアルキルであり;
nは、0、1、2または3であり;
R21、R22、R23、R24、R25、R26、R27、R28、R35、R36、R37、R38、およびR39は独立して、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれ;そして、
Yは、結合、炭素、または酸素から選ばれ;但し、Yが結合である場合には、KおよびLは存在せず、そしてMは、アリールまたはヘテロアリールから選ばれ;そして、Yが酸素である場合には、KおよびLは存在せず、そしてMは、水素、アルコキシアルキル、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、またはヘテロアリールから選ばれ;
但し、少なくとも1つのイメージング分子は式(IV)中に存在する]
である。
Jは、N(R27)、S、O、C(=O)、C(=O)O、NHCH2CH2O、結合、またはC(=O)N(R27)から選ばれ;
Kは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれ;
存在する場合には、Lは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれ;
存在する場合には、Mは、水素、アルコキシアルキル、アルキルオキシ、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、ヘテロアリール、またはイメージング分子から選ばれるか;あるいは、
LおよびMはそれらが結合する原子と一緒になって、3−または4−員の炭素環を形成し;
TおよびUは独立して、水素、アルコキシ、アルコキシアルキル、場合によりイメージング分子で置換されたC1〜C6アルキル、ハロ、またはイメージング分子から選ばれるか;あるいは、
TおよびUはそれらが結合する炭素原子と一緒になって、酸素、窒素または硫黄から選ばれる0〜2個のヘテロ原子を含有する5−または6−員の芳香環または非芳香環を形成し、ここで、該環は場合により、独立して場合によりイメージング分子で置換されたC1〜C6アルキルまたはイメージング分子から選ばれる、1、2または3個の置換基で置換され;
nは、0、1、2または3であり;
R21、R22、R23、R24、R25、R26、R27、およびR34は独立して、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれ;
Yは、結合、炭素、または酸素から選ばれ;但し、Yが結合である場合には、KおよびLは存在せず、そしてMは、アリールまたはヘテロアリールから選ばれ;そして、Yが酸素である場合には、KおよびLは存在せず、そしてMは、水素、アルコキシアルキル、アリール、場合によりイメージング分子で置換されたC1〜C6アルキル、またはヘテロアリールから選ばれ;
但し、少なくとも1つのイメージング分子は式(V)中に存在する]
である。
R23、R24、R25、R26、およびR34は独立して、水素、場合によりイメージング分子で置換されたC1〜C6アルキル、またはイメージング分子から選ばれ;
但し、少なくとも1つのイメージング分子は式(VI)中に存在する]
である。
本発明の開示の核医学造影剤は、11C、13N、18F、123I、125I、99mTc、95Tc、111In、62Cu、64Cu、67Ga、および68Gaを含む。11C−パルミチン酸が脂肪酸酸化をプローブするために使用され、そして11C−酢酸が心筋中の酸化代謝を評価するために使用されている(Circulation 1987, 76, 687-696)。13N−アンモニアが、心筋灌流をイメージするために広く使用されている(Circulation 1989, 80, 1328-37)。18Fをベースとする薬剤が、低酸素症および癌のためのイメージング剤として使用されている(Drugs of the Future 2002, 27, 655-667)。15−(p−(123I)−ヨードフェニル)−ペンタンデカン酸、および15−(p−(123I)−ヨードフェニル)−3(R,S)−メチルペンタンデカン酸は、2個のヨウ素化剤(これは、心筋代謝をイメージングするのに使用する)が挙げられる。1実施態様において、本発明の造影剤において使用するイメージング分子は18Fである。本発明の開示の更なるイメージング分子は、1つ以上のX−線吸収剤、または原子番号が20以上の「重」原子を含み得て、更に親分子および該X−線吸収原子と間の任意の連結分子を含有する。X−線造影剤において用いられることの多い重原子はヨウ素である。最近、金属キレートを含むX−線造影剤(米国特許第5,417,959号)、および複数の金属イオンを含むポリキレート(米国特許第5,679,810号)が開示されている。より最近では、多重核クラスター複合体がX−線造影剤として開示されている(米国特許第5,804,161号、PCT W091/14460、およびPCT WO 92/17215)。本発明の開示のある実施態様において、該X−線造影剤において使用する具体的な金属は例えば、Re、Sm、Ho、Lu、Pm、Y、Bi、Pd、Gd、La、Au、Au、Yb、Dy、Cu、Rh、AgおよびIrを含む。
99mTcを用いて化合物を標識する多数の方法が知られ、例えば該化合物の直接な標識、またはキレート分子(「キレート因子(chelator)」)の取り込みを含む。1実施態様において、キレート因子は、DADT、MAG3、MAMA、PAMA、またはDOTAである。
各A1は独立して、−NR46R47、−NHR53、−SH、−S(Pg)、−OH、−PR46R47、−P(O)R48R49、またはMC−1と結合する化合物との結合、から選ばれ;
各A2は独立して、N(R53)、N(R46)、S、O、P(R46)、または−OP(O)(R48)O−から選ばれ;
A3はNであり;
A4は、OH、またはOC(=O)C1〜C20アルキルであり;
A5は、OC(=O)C1〜C20アルキルであり;
各Eは独立して、0〜3個のR50で置換されたC1〜C16アルキレン、0〜3個のR50で置換されたC6〜C10アリーレン、0〜3個のR50で置換されたC3〜C10シクロアルキレン、0〜3個のR50で置換されたヘテロサイクリル−C1〜C10アルキレン、0〜3個のR50で置換されたC6〜C10アリール−C1〜C10アルキレン、または0〜3個のR50で置換されたヘテロサイクリレンから選ばれ;
E1は、結合またはEから選ばれ;
各E2は独立して、0〜3個のR50で置換されたC1〜C16アルキル、0〜3個のR50で置換されたC6〜C10アリール、0〜3個のR50で置換されたC3〜C10シクロアルキル、0〜3個のR50で置換されたヘテロサイクリル−C1〜C10アルキル、0〜3個のR50で置換されたC6〜C10アリール−C1〜C10アルキル、0〜3個のR50で置換されたC1〜C10アルキル−C6〜C10アリール、または0〜3個のR50で置換されたヘテロサイクリルから選ばれ;
E3は、1〜3個のR59で置換されたC1〜C10アルキレンであり;
Pgは、チオール保護基であり;
R46およびR47は各々独立して、MC−1と結合する化合物との結合、水素、0〜3個のR50で置換されたC1〜C10アルキル、0〜3個のR50で置換されたアリール、0〜3個のR50で置換されたC3〜C10シクロアルキル、0〜3個のR50で置換されたヘテロサイクリル−C1〜C10アルキル、0〜3個のR50で置換されたC6〜C10アリール−C1〜C10アルキル、または0〜3個のR50で置換されたヘテロサイクリルから選ばれ;
R46およびR47は各々独立して、MC−1と結合する化合物との結合、−OH、0〜3個のR50で置換されたC1〜C10アルキル、0〜3個のR50で置換されたアリール、0〜3個のR50で置換されたC3〜C10シクロアルキル、0〜3個のR50で置換されたヘテロサイクリル−C1〜C10アルキル、0〜3個のR50で置換されたC6〜C10アリール−C1〜C10アルキル、または0〜3個のR50で置換されたヘテロサイクリルから選ばれ;
各R50は独立して、MC−1と結合する化合物との結合、=O、ハロ、トリフルオロメチル、シアノ、−CO2R51、−C(=O)R51、−C(=O)N(R51)2、−CHO、−CH2OR51、−OC(=O)R51、−OC(=O)OR51、−OR51、−OC(=O)N(R51)2、−NR51C(=O)R51、−NR51C(=O)OR51、−NR51C(=O)N(R51)2、−NR51SO2(R51)2、−NR51SO2R51、−SO3H、−SO2R51、−SR51、−S(=O)R51、−SO2(R51)2、−N(R51)2、−NHC(=S)NHR51、=NOR51、NO2、−C(=O)NHOR51、−C(=O)NHN(R51)2、−OCH2CO2H、2−(1−モルホリノ)エトキシ、C1〜C5アルキル、C2〜C4アルケニル、C3〜C6シクロアルキル、C3〜C6シクロアルキルメチル、C2〜C6アルコキシアルキル、0〜2個のR51で置換されたアリール、またはヘテロサイクリルから選ばれ;
各R51は独立して、MC−1と結合する化合物との結合、水素、C1〜C6アルキル、フェニル、ベンジル、またはC1〜6アルコキシから選ばれ;
R53は、金属との配位結合であり;
各R59は、R61、=O、−CO2R60、−C(=O)R60、−C(=O)N(R60)2、−CH2OR60、−OR60、−N(R60)2、またはC2〜C4アルケニルから選ばれ;
各R60は独立して、R61、水素、C1〜C6アルキル、フェニル、ベンジル、またはトリフルオロメチルから選ばれ;
R61は、MC−1と結合する化合物との結合であり;
ここで、A1、R46、R47、R48、R49、R50、R51、またはR61の少なくとも1つは、MC−1と結合する化合物との結合である。
典型的に、18F標識化合物は、適当な脱離基のSn2置換によって製造する。これらの脱離基は、スルホン酸エステル(例えば、トルエンスルホネート(トシレート、TsO)、メタンスルホネート(メシレート、MsO)、またはトリフルオロメタンスルホネート(トリフレート、TfO))であることが好ましい。該脱離基はまた、ハライド、ホスフィンオキシド(ミツノブ反応による)、または内部脱離基(例えば、エポキシド、または環状スルフェート)でもあり得る。これらの化合物は、非常に活性化された乾燥K18F(これは、クリプタンド(例えば、クリプトフィックス[2.2.2])の添加によって「ホッター(hotter)」とする)から製造する。精製は通常、逆相クロマトグラフィー精製(Sep-Pak)による塩の除去による。
本発明の開示の造影剤は、イメージングの方法において使用し得る。ここで、該造影剤を患者に、注射、注入、またはいずれかの他の公知の方法によって投与し、そして関心あう事象が存在する患者の領域をイメージングすることを含む、イメージング方法を含む。
いずれかの特定の基における炭素原子の数は、基について詳説する前に記載する。例えば、用語「C6〜C10アリール」とは、6〜10個の炭素原子を含有するアリール基を示す。用語「C6〜C10アリール−C1〜C10アルキル」とは、1〜10個の炭素原子のアルキル基で親分子と結合する6〜10個の炭素原子のアリール基を意味する。
実施例1A
4−[4−(2−ヒドロキシエチル)フェニル]−4−オキソ−酪酸メチルエステルの製造
4−[4−(2−ヒドロキシエチル)フェニル]酪酸メチルエステルの製造:
4−{4−[2−(キナゾリン−4−イルオキシ)エチル]フェニル}酪酸メチルエステルの製造:
4−{4−[2−(キナゾリン−4−イルオキシ)エチル]フェニル}ブタン−1−オールの製造:
トルエン−4−スルホン酸 4−{4−[2−(キナゾリン−4−イルオキシエチル]フェニル}ブチルエステルの製造:
4−{2−[4−(4−フルオロブチル)フェニル]エトキシ}キナゾリンの製造:
実施例2A
酪酸4−フェニルブチルエステルの製造
4−(4−ヒドロキシブチル)安息香酸メチルエステルの製造:
4−[4−(tert−ブチルジメチルシラニルオキシ)ブチル]安息香酸メチルエステルの製造:
{4−[4−(tert−ブチルジメチルシラニルオキシ)ブチル]フェニル}−メタノールの製造:
2−tert−ブチル−5−{4−[4−(tert−ブチルジメチルシラニルオキシ)ブチル]ベンジルオキシ}−4−クロロ−2H−ピリダジン−3−オンの製造:
2−tert−ブチル−4−クロロ−5−[4−(4−ヒドロキシ-ブチル)−ベンジルオキシ]−2H−ピリダジン−3−オンの製造:
トルエン−4−スルホン酸 4−[4−(1−tert−ブチル−5−クロロ−6−オキソ−1,6−ジヒドロピリダジン−4−イルオキシメチル)−フェニル]−ブチルエステルの製造:
2−tert−ブチル−4−クロロ−5−(4−(4−フルオロブチル)ベンジル)オキシ 3(2H)ピリダジノンの製造:
(±)−1−tert−ブチルジメチルシリルオキシ−2−ヒドロキシブタンの製造:
(±)−4−(1−tertブチルジメチルシリルオキシ ブタ−2−オキシ)メチルベンゾエートの製造:
(±)−4−(1−tertブチルジメチルシリルオキシブタ−2−オキシ)ベンジルアルコールの製造:
(±)−2−tert−ブチル 4−クロロ 5−(4−(1−tert−ブチルジメチルシリルオキシ ブタ−2−オキシ)ベンジル)オキシ 3(2H)−ピリダジノンの製造:
(±)−2−tert−ブチル−4−クロロ−5−(4−(1−ヒドロキシ−ブタ−2−オキシ)ベンジル)オキシ−3(2H)−ピリダジノンの製造:
(±)−2−tert−ブチル 4−クロロ 5−(4−(1−トシルオキシ−ブタ−2−オキシ)ベンジル)オキシ 3(2H)−ピリダジノンの製造:
(±)−2−tert−ブチル−4−クロロ 5−(4−(1−フルオロ−ブタ−2−オキシ)ベンジル)オキシ−3(2H)−ピリダジノンの製造:
4−(3−ヒドロキシプロポキシ)−安息香酸メチルエステルの製造:
4−[3−(tert−ブチルジメチルシラニルオキシ)プロポキシ]安息香酸メチルエステルの製造:
{4−[3−(tert−ブチルジメチルシラニルオキシ)プロポキシ]フェニル}メタノールの製造:
2−tert−ブチル−4−クロロ−5−{4−[3−(tert−ブチルジメチルシラニルオキシ)プロポキシ]ベンジルオキシ}−2H−ピリダジン−3−オンの製造:
2−tert−ブチル−4−クロロ−5−[4−(3−ヒドロキシプロポキシ)−ベンジルオキシ]−2H−ピリダジン−3−オンの製造:
トルエン−4−スルホン酸 3−[4−(1−tert−ブチル−5−クロロ−6−オキソ−1,6−ジヒドロピリダジン−4−イルオキシメチル)フェノキシ]プロピルエステルの製造:
2−tert−ブチル−4−クロロ−5−[4−(3−フルオロプロポキシ)ベンジルオキシ]−2H−ピリダジン−3−オンの製造:
4−(2−ヒドロキシエトキシメチル)安息香酸メチルエステルの製造:
4−[2−(tert−ブチルジメチルシラニルオキシ)エトキシメチル]安息香酸メチルエステルの製造:
{4−[2−(tert−ブチルジメチルシラニルオキシ)エトキシメチル]フェニル}メタノールの製造:
2−tert−ブチル−5−{4−[2−(tert−ブチルジメチルシラニルオキシ)エトキシメチル]ベンジルオキシ}−4−クロロ−2H−ピリダジン−3−オンの製造:
2−tert−ブチル−4−クロロ−5−[4−(2−ヒドロキシエトキシメチル)ベンジルオキシ]−2H−ピリダジン−3−オンの製造:
トルエン−4−スルホン酸 2−[4−(1−tert−ブチル−5−クロロ−6−オキソ−1,6−ジヒドロピリダジン−4−イルオキシメチル)−ベンジルオキシ]−エチルエステルの製造:
2−tert−ブチル−4−クロロ−5−[4−(2−フルオロ−エトキシメチル)−ベンジルオイ(benzyloy)]−2H−ピリダジン−3−オンの製造:
1−(4−ヒドロキシメチルフェノキシ)プロパン−2−オンの製造:
1−(4−ヒドロキシメチル−フェノキシ)−プロパン−2−オールの製造:
2−tert−ブチル−4−クロロ−5−[4−(2−ヒドロキシプロポキシ)ベンジルオキシ]−2H−ピリダジン−3−オンの製造:
トルエン−4−スルホン酸 2−[4−(1−tert−ブチル−5−クロロ−6−オキソ−1,6−ジヒドロピリダジン−4−イルオキシメチル)−フェノキシ]−1−メチルエチルエステルの製造:
2−tert−ブチル−4−クロロ−5−[4−(2−フルオロプロポキシ)ベンジルオイ]−2H−ピリダジン−3−オンの製造:
4−(3−オキソブチル)安息香酸メチルエステルの製造:
2−tert−ブチル−4−クロロ−5−[4−(3−ヒドロキシブチル)ベンジルオキシ]−2H−ピリダジン−3−オンの製造:
トルエン−4−スルホン酸 3−[4−(1−tert−ブチル−5−クロロ−6−オキソ−1,6−ジヒドロ−ピリダジン−4−イルオキシメチル)−フェニル]−1−メチルプロピルエステルの製造:
2−tert−ブチル−4−クロロ−5−[4−(3−フルオロブチル)ベンジルオキシ]−2H−ピリダジン−3−オンの製造:
4−[2−ヒドロキシエトキシメチル]安息香酸メチルエステル 4重水素(tetradeuterate)の製造:
4−[2−(tert−ブチルジメチルシラニルオキシ)エトキシメチル]安息香酸メチルエステル 4重水素の製造:
{4−[2−(tert−ブチルジメチルシラニルオキシ)エトキシメチル]フェニル}メタノール 6重水素の製造:
2−tert−ブチル−4−クロロ−5−{4−[2−(tert−ブチルジメチルシラニルオキシ)エトキシメチル]ベンジルオキシ}−2H−ピリダジン−3−オン 6重水素の製造:
2−tert−ブチル−4−クロロ−5−[4−(2−ヒドロキシエトキシメチル)ベンジルオキシ]−2H−ピリダジン−3−オン 6重水素の製造:
トルエン−4−スルホン酸 2−[4−(1−tert−ブチル−5−クロロ−6−オキソ−1,6−ジヒドロピリダジン−4−イルオキシメチル)-ベンジルオキシ]エチルエステル 6重水素の製造;
該研究において使用するフッ素−18(18F)は、H2 18Oとしてエンリッチな酸素−18O(18O)を、PETnet(Woburn、MA)による約10MeVプロトンを用いてプロトン照射することにより、生成する。この核反応についての表現は、O18(p,γ)18Fとする。
次の工程は、フェナザキンおよびピリダベンのアナログの18Fを用いた放射標識を記載する。上記の通り、これらの工程は、該化合物の各々について同じとした。以下の反応式は、18F−フェナザキンおよびピリダベンのアナログの全てについての代表的なシナリオを示す。
ジクロロエタン(30mL)に溶解するロテノン(Rotenone)(5.0g、12.7mmol)を、ジクロロメタン(32.7mL)中の三臭化ホウ素(3.15g、12.7mmol)の冷(−10℃)溶液に素早く加える。該反応混合物を正確に2分間撹拌し、次いで乾固するまで蒸発させた。得られた褐色粗物質を、最少量のメタノール中に溶解し、そして0℃まで冷却して結晶化を開始する。褐色結晶を集め、そして乾燥して4’−ブロモ−ロタ−2’−エノン酸(3.24g)を得る。
酸化銀(1.0g、4.23mmol)を、アセトン(80mL)中に溶解した4’−ブロモ−ロタ−2’エノン酸(2.0g、4.24mmol)の溶液に加える。添加の完結後に、該反応混合物を暗中で撹拌し続ける。24時間後に、該反応混合物をセライトを通してろ過し、そして該ろ液を濃縮して黄色油状物を得る。該粗物質を最少量のジクロロメタンに溶解し、そして0℃まで冷却して結晶化を開始する。黄色結晶の4’−ヒドロキシロタ−2’エノン酸(1.0g)を集めることができる。
固体PhSe−Cl(370.87mg、1.94mmol)を、ジクロロメタン(20mL)中の4−ヒドロキシ−ロタ−2’エノン酸(725.5mg、1.71mmol)の冷却(−30℃)溶液に加える。添加が完結後に、該反応混合物を室温まで2時間かけて昇温させ、そして室温で更に1時間撹拌し続ける。総反応時間が3時間後に、該反応混合物を濃縮して、黄色油状物を得る。該粗物質をTHF(20mL)に溶解し、そして0℃まで冷却する。過酸化水素(水中30%、0.354mL)を加える。添加が完結後に、該反応混合物を0℃で1時間撹拌し、次いで室温で終夜撹拌する。翌日に、該反応混合物をジエチルエーテルを用いて希釈する。該有機層を分離し、そして5% NaHCO3(2×)を用いて洗浄し、Na2SO4を用いて乾燥し、そして濃縮して黄色アモルファス固体の(6aS,12aS)−7’−ヒドロキシデグエリンを得る。
ジクロロメタン(1.5mL)中の(6aS,12aS)−7’−ヒドロキシデグエリン(30mg、0.073mmol)の撹拌溶液に、TsCl(15.3mg、0.080mmol)およびピリジン(6.47μL、0.080mmol)を加える。添加が完結後に、該反応混合物を室温で撹拌し続ける。48時間後に、該反応はLCMSに従って〜50%完結し、そしてこのものを濃縮する。該粗物質をシリカゲルクロマトグラフィー(100% ジクロロメタン〜25% アセトン/ジクロロメタンの勾配)を用いて精製して、黄色油状物の(6aS,12aS)−7’−トルエンスルホニルデグエリンを得る。
ジクロロメタン(0.5mL)中の(6aS,12aS)−7’−ヒドロキシデグエリン(50mg、0.122mmol)の撹拌溶液に、MsCl(9.48μL、0.122mmol)およびトリエチルアミン(17.0μL、0.122mmol)を加える。添加が完結後に、該反応混合物を室温で撹拌し続ける。3時間後に、該反応はわずか〜80%の完結であるので、更なる当量のMsClおよびトリエチルアミンを加える。24時間後に、該反応は完結し、そして水を用いて希釈する。該水層をジクロロメタンを用いて抽出した。合わせた有機層の全てをNa2SO4を用いて乾燥し、ろ過し、そして濃縮して黄色油状物を得る。シリカゲルクロマトグラフィー精製(100% ジクロロメタン〜5% アセトン/ジクロロメタンの勾配)により、黄色油状物の(6aS,12aS)−7’−メタンスルホニルデグエリン(48mg)を得る。
シラン処理ストッパーを有する薄肉(thin-wall)10mLシラン処理採血菅(silanized vacutainer)を、水酸化テトラブチルアンモニウム(5μL、40%w/vの水溶液)および18F−水溶液(10mCi、200μL)を満たす。得られた混合物を、窒素気流下、100℃で乾固するまで蒸発させる。該残渣を更に、CH3CN(3×200μL)の添加および蒸発を繰り返すことによって、乾燥する。別のアリコートのCH3CNを加え、そして加熱しながら真空下で濃縮する。完全な溶媒の除去の前に、THF(150μL)を加え、該バイアルをクリンプせず(uncrimped)、そして(6aS,12aS)−7’−メタンスルホニルデグエリン(2mg)を1回で加える。該バイアルを再度封し、そして65℃で30分間加熱する。冷却後に、該バイアルを水(4mL)を用いて希釈し、そしてシリカゲルカートリッジ(前処理したWaters Light C-18 Sep-Pak)を通して、試料をロードする。該カートリッジを水ですすぎ、そしてCH3CN(2mL)を用いて溶出する。該アセトニトリルを蒸発させ、そして該残渣をHPLCによって精製して、純粋な担体なしの(6aS,12aS)−7’−[18F]フルオロデグエリンを得る。
シラン処理ストッパーを有する薄肉10mLシラン処理採血菅を、水酸化テトラブチルアンモニウム(5μL、40%w/vの水溶液)および18F−水溶液(10mCi、200μL)を満たす。得られた混合物を、窒素気流下、100℃で蒸発して乾固する。該残渣を更に、CH3CN(3×200μL)の添加および蒸発を繰り返すことによって乾燥する。更なるアリコートのCH3CNを加え、そして加熱しながら真空下で濃縮する。完全な溶媒の除去の前に、THF(150μL)を加え、該バイアルをクリンプせず、そして(6aS,12aS)−7’−トルエンスルホニルデグエリン(2mg)を1回で加える。該バイアルを再度封し、そして65℃で30分間加熱する。冷却後に、該バイアルを水(4mL)を用いて希釈し、そしてシリカゲルカートリッジ(前処理したWaters Light C-18 Sep-Pak)を通して、試料をロードする。該カートリッジを水ですすぎ、そしてCH3CN(2mL)を用いて溶出する。該アセトニトリルを蒸発させ、そして該残渣をHPLCによって精製して、純粋な担体(6aS,12aS)−7’−[18F]フルオロデグエリンを得る。
固体PhSe−Cl(195mg、0.972mmol)を、ジクロロメタン(10.5mL)中の(−)−ロタ−2’エノン酸(350mg、0.884mmol)の冷却(−30℃)溶液に加える。添加が完結後に、該反応混合物を室温まで2時間かけて昇温させ、そして室温で更に1時間撹拌する。総反応時間が3時間後に、該反応混合物を濃縮して、黄色油状物を得る。該粗物質をTHF(10.5mL)中に溶解し、そして0℃まで冷却する。過酸化水素(30%水溶液、0.177mL)を加える。添加が完結後に、該反応混合物を0℃で1時間撹拌し、次いで室温で終夜撹拌し続ける。翌日に、該反応混合物をジエチルエーテルを用いて希釈する。該有機層を分離し、そして5% NaHCO3(2×)を用いて洗浄し、Na2SO4を用いて乾燥し、そして濃縮して黄色アモルファス固体の(6aS,12aS)−デグエリンを得る。
ジクロロメタン(0.5mL)中の(6aS)−デグエリンエノールエーテル(50mg、0.123mmol)の冷却(0℃)溶液に、m−CPBA(45mg、0.184mmol)を加える。添加が完結後に、該反応混合物を室温で撹拌し続ける。6.5時間後に、該反応液を水を用いて希釈する。該水層をジクロロメタンを用いて抽出する。合わせた有機層の全てをNa2SO4を用いて乾燥し、濃縮し、そしてシリカゲルクロマトグラフィー(100% ジクロロメタン〜30% ジクロロメタンの勾配)を用いて精製して、(6aS)−4’,5’−ジヒドロ−4’,5’エポキシデグエリンエノールエーテルを得る。
シラン処理ストッパーを有する薄肉10mLシラン処理採血菅を、水酸化テトラブチルアンモニウム(5μL、40%w/vの水溶液)および18F−水溶液(10mCi、200μL)で満たす。得られた混合物を、窒素気流下、100℃で蒸発させて乾固させる。該残渣を更に、CH3CN(3×200μL)の添加および蒸発を繰り返すことによって乾燥する。更なるアリコートのCH3CNを加え、そして加熱せずに真空下で濃縮する。完全な溶媒の除去の前に、THF(150μL)を加え、該バイアルをクリンプせず、そして(6aS)−4’,5’−ジヒドロ−4’,5’エポキシデグエリンエノールエーテル(2mg)を1回で加える。該バイアルを再度封し、そして65℃で30分間加熱する。室温まで冷却後に、トリフルオロ酢酸(500mL)および水(300mL)の溶液をゆっくりと加える。該反応容器を閉じて、そして60℃で2分間放置する。室温まで冷却後に、該バイアルを水(4mL)を用いて希釈し、そしてシリカゲルカートリッジ(前処理したWaters Light C-18 Sep-Pak)を通して、試料をロードする。該カートリッジを水ですすぎ、そしてCH3CN(2mL)を用いて溶出する。該アセトニトリルを蒸発させ、そして該残渣をHPLCによって精製して、純粋な担体なしの(6aS,12aS)−4’,5’−ジヒドロ−4’[18F]フルオロ,5’ヒドロキシデグエリンを得る。
[18F]Fは、[18O]水(>94%、400μL)を銀標的チャンバー中で、103cm AVFサイクロトロンからの17meVプロトンで照射することによって調製する。典型的な照射は、約18GBq[18F]フルオリドを与える10mAのビーム電流を用いる45分間の期間とする。照射後に、該標的水を、シリコンチューブで合成装置まで運ぶ。この装置はホウケイ酸容器(5mL)から構成され、これは、アセトニトリル(1mL)中の炭酸カリウム(5mg、36μmmol)、およびK2.2.2(18mg、48μmol)を含む。該標的水を、減圧下およびHeフロー下で蒸発させる。3部のアセトニトリルを110℃で加える。該反応チャンバーを室温まで冷却し、そしてアセトニトリル(1mL)中のジブロモメタン(50μL)を乾燥18F/K2.2.2−混合物に加える。該反応混合物を110℃で再度加熱し、そして該揮発性生成物を、Heをキャリヤーとして、プレパラティブGCに移した。該カラムを100℃まで加熱し、そして[18F]CH2BrFを、溶媒および他の試薬から分離する。
ジクロロメタン(1.5mL)中の(6aS)−4’,5’−ジヒドロ−5’−ヒドロキシデグエリンエノールエーテル(31mg、0.073mmol)の撹拌溶液に、TsCl(15.3mg、0.080mmol)およびピリジン(6.47μL、0.080mmol)を加える。添加が完結後に、該反応混合物を室温で撹拌し続ける。28時間後に、該反応はLCMSによれば完結し、そしてこのものを濃縮する。該粗物質をシリカゲルクロマトグラフィー(100% ジクロロメタン〜25% アセトン/ジクロロエタンの勾配)を用いて精製して、(6aS)−4’,5’−ジヒドロ−5’トルエンスルホニルデグエリンエノールエーテルを得る。
Me2CO(6mL)中の2,4−ジヒドロキシ−5−ニトロ−ベンズアルデヒド(10.61g、58mmol)の溶液を、ピリジン(2.29g、2.34mL、29mmol)中の3−メチル−ブタ−2−エナール(enal)(4.00g、29mmol)の撹拌溶液に、120℃で5.5時間かけて加える。添加が完結後に、加熱を更に18時間続ける。該Me2COを蒸発させ、そして該ピリジンをトルエンとの共沸蒸留によって除去して、粗生成物を得る。該粗生成物をシリカゲルクロマトグラフィー(1% 酢酸エチル/ヘキサン)を用いて精製して、5−ヒドロキシ−2,2−ジメチル−8−ニトロ−2H−クロメン−6−カルバルデヒドを得る。
フレーム乾燥10mL丸底フラスコに、4−(3,4−ジメトキシフェニルオキシ)−1−(5−メトキシ−2,2−ジメチル−8−ニトロ−2H−クロメン−6−イル)−ブタ−2−イン−1−オン(61.6mg、0.135mmol)およびPtCl2(1.8mg、5mol%)を加える。該フラスコを排除し、そしてアルゴンを用いて3回フラッシュし、続いてトルエン(1.8mL、0.1m)を加える。該反応液を55℃で10時間撹拌し、次いで濃縮する。該粗物質をシリカゲルクロマトグラフィー(7:3のヘキサン:酢酸エチル)を用いて精製して、(6,7−ジメトキシ−2H−クロマン−3−イル)−(5−メトキシ−2,2−ジメチル−8−ニトロ−2H−クロメン−6−イル)−メタノンを得る。
フレーム乾燥10mL丸底フラスコに、(6,7−ジメトキシ−2H−クロマン−3−イル)−(5−メトキシ−2,2−ジメチル−7−ニトロ−2H−クロメン−6−イル)−メタノン(50.2mg、0.111mmol)およびジクロロメタン(2.0mL)を加える。該溶液を−78℃まで冷却し、そして三塩化ホウ素(0.133mL、1M ジクロロメタン溶液、0.133mmol)を加える。1時間撹拌後に、該反応液を飽和NH4Clを用いてクエンチし、酢酸エチルを用いて抽出し、Na2SO4を用いて乾燥し、そして濃縮する。該粗物質をEtOHに溶解し、酢酸カリウムで飽和とし、そして1時間還流する。室温まで冷却後に、酢酸エチルおよび水を該反応混合物に加える。該水層を酢酸エチルを用いて抽出する。合わせた有機層をブラインを用いて洗浄し、Na2SO4を用いて乾燥し、そして濃縮する。該粗物質をシリカゲルパッド(3:1のヘキサン:酢酸エチル)を用いてろ過して、(+/−)−11−ニトロデグエリンを得る。
5−N−(4−tert−ブチルベンジル)カルボキサミド−3−(メトキシカルボニル)−1−メチルピラゾールの製造:
ジクロロメタン(100mL)中の4−tert−ブチル−3−ニトロ安息香酸(0.1mol)、ヒドロキシベンゾトリアゾール(HOBt、0.12mol)、およびジシクロヘキシルカルボジイミド(DCC、0.11mol)の混合物を室温で撹拌し、その間、2−プロパノール中のアンモニアの溶液(2.0M、75mL、0.12mol)を素早く加える。該混合物を室温で2時間撹拌し、そしてこのものをNaHCO3水溶液(5%、200mL)中にそそぐ。相分離し、そして該水層をジクロロメタンを用いて抽出する(2×200mL)。該有機物を合わせて洗浄し(2×200mL、5% NaHCO3水溶液)、乾燥し(飽和NaCl水溶液、Na2SO4)、ろ過し、そして濃縮する。該生成物を再結晶(EtOH−水から)して、純粋な4−tert−ブチル−3−ニトロベンズアミドを得る。
2−tert−ブチル−4,5−ジクロロ−3(2H)−ピリダジノンの製造:
DMF(4mL)中の2−tert−ブチル−4−クロロ−5−チオ−3(2H)−ピリダジノン(220mg)に、4−tert−ブチルベンジルブロミド(226mg、1mmol)およびNa2CO3を加えた。該反応混合物を室温で16時間撹拌し、その後に、酢酸エチル中に抽出し、水洗し、そしてカラムクロマトグラフィー(シリカゲル;溶出液として、酢酸エチル/ヘキサン)によって精製した。これにより、上記の化合物を得た。
丸底フラスコを、2−tert−ブチル−4−クロロ−5−(4−tert−ブチルベンジル)チオ3(2H)−ピリダジノン(100mg、0.27mmol)で満たし、そしてこのものに、フッ化カリウム(23.4mg、0.40mmol)およびジメチルスルホキシド(2mL)を加える。このものを、120℃まで6時間加熱する。次いで、該反応混合物を水中にそそぎ、そして酢酸エチルを用いて抽出する。このものを水洗し、そして乾燥する。フラッシュクロマトグラフィー(シリカゲル;酢酸エチル/ヘキサン)による精製により、上記の化合物を得る。
18水(350mg)中の18F(500mCi)を含有する5mL反応バイアルに、クリプトフィックス(10mg)、炭酸カリウム(1mg)、水(0.005mL)、およびアセトニトリル(0.95mL)を含有する溶液(1mL)を加える。該バイアルを加熱して全ての溶媒を除去し、そして乾燥アセトニトリル(1mL)を該バイアルに加える。このものはまた、蒸発によって除去する。次いで、アセトニトリル中の2−tert−ブチル−4−クロロ−5−(4−tert−ブチルベンジル)チオ3(2H)−ピリダジノン(5mg)をそれに加える。該バイアルを封し、そして100℃で30分間加熱する。該混合物をジクロロメタンを用いて希釈し、そしてSep−Pakを通し、テトラヒドロフランを用いて溶出する。該溶媒を蒸発させて、上記の化合物を得る。
2−tert−ブチル−4−クロロ−5−(4−(4−ヒドロキシブチル)ベンジルチオ−3(2H)−ピリダジノン(0.15g、0.39mmol)を満たした15mL丸底フラスコに、ピリジンを加える。次いで、トルエンスルホニルクロリド(88.9mg、0.42mmol)をそれに加え、そして該混合物を2時間撹拌する。該反応混合物を酢酸エチルを用いて希釈し、5% 硫酸銅溶液、次いで水を用いて洗浄し、そして乾燥する。該溶媒をロータリーエバポレーターを用いて除去後に、該粗物をフラッシュクロマトグラフィー(溶出混合物として、酢酸エチル−ヘキサンを使用する)によって精製する。
4−クロロキナゾリンの製造:
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Cited By (2)
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JP2013047277A (ja) * | 2004-02-13 | 2013-03-07 | Bristol-Myers Squibb Pharma Co | 心筋灌流イメージングのための造影剤 |
JP2014218525A (ja) * | 2004-02-13 | 2014-11-20 | ブリストル−マイヤーズ・スクイブ・ファーマ・カンパニーBristol−Myers Squibb Pharma Company | 心筋灌流イメージングのための造影剤 |
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