WO1991012024A1 - Triarylmethyl radicals and the use of inert carbon free radicals in mri - Google Patents
Triarylmethyl radicals and the use of inert carbon free radicals in mri Download PDFInfo
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- WO1991012024A1 WO1991012024A1 PCT/EP1991/000285 EP9100285W WO9112024A1 WO 1991012024 A1 WO1991012024 A1 WO 1991012024A1 EP 9100285 W EP9100285 W EP 9100285W WO 9112024 A1 WO9112024 A1 WO 9112024A1
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- -1 Triarylmethyl radicals Chemical class 0.000 title claims description 96
- 150000001723 carbon free-radicals Chemical class 0.000 title claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 148
- 150000003254 radicals Chemical class 0.000 claims description 122
- 239000000203 mixture Substances 0.000 claims description 115
- 150000001875 compounds Chemical class 0.000 claims description 78
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 40
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 26
- 239000002872 contrast media Substances 0.000 claims description 23
- 230000007704 transition Effects 0.000 claims description 22
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 21
- 239000002243 precursor Substances 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 125000005039 triarylmethyl group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 230000005855 radiation Effects 0.000 claims description 12
- 230000009467 reduction Effects 0.000 claims description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 11
- 238000002595 magnetic resonance imaging Methods 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 230000005291 magnetic effect Effects 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 230000003381 solubilizing effect Effects 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 150000002902 organometallic compounds Chemical class 0.000 claims description 4
- 150000002978 peroxides Chemical class 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 239000001569 carbon dioxide Substances 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 230000002708 enhancing effect Effects 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 3
- 230000006698 induction Effects 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000005188 oxoalkyl group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 2
- 238000004435 EPR spectroscopy Methods 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 238000011835 investigation Methods 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims 2
- BGCPLWWYPZAURQ-UHFFFAOYSA-N 5-[[5-chloro-2-(2,2,6,6-tetramethylmorpholin-4-yl)pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methylbutyl)-1-methylbenzimidazol-2-one Chemical compound ClC=1C(=NC(=NC=1)N1CC(OC(C1)(C)C)(C)C)NC1=CC2=C(N(C(N2CCC(C)(C)O)=O)C)C=C1 BGCPLWWYPZAURQ-UHFFFAOYSA-N 0.000 claims 1
- 150000001491 aromatic compounds Chemical class 0.000 claims 1
- 125000001979 organolithium group Chemical group 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 384
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 212
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 168
- 239000007983 Tris buffer Substances 0.000 description 154
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 129
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 122
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 115
- 239000000243 solution Substances 0.000 description 95
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 90
- 229960004132 diethyl ether Drugs 0.000 description 88
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 79
- 238000005160 1H NMR spectroscopy Methods 0.000 description 78
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 70
- 239000011541 reaction mixture Substances 0.000 description 69
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 67
- 239000000047 product Substances 0.000 description 64
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
- 239000012074 organic phase Substances 0.000 description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 49
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 239000002904 solvent Substances 0.000 description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- 239000012071 phase Substances 0.000 description 44
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 40
- 239000000377 silicon dioxide Substances 0.000 description 40
- 238000003756 stirring Methods 0.000 description 39
- 238000001816 cooling Methods 0.000 description 38
- 229910052786 argon Inorganic materials 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 35
- 229910052681 coesite Inorganic materials 0.000 description 33
- 229910052906 cristobalite Inorganic materials 0.000 description 33
- 239000011734 sodium Substances 0.000 description 33
- 229910052682 stishovite Inorganic materials 0.000 description 33
- 229910052905 tridymite Inorganic materials 0.000 description 33
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 31
- 238000000804 electron spin resonance spectroscopy Methods 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 239000011701 zinc Substances 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- AASUFOVSZUIILF-UHFFFAOYSA-N diphenylmethanone;sodium Chemical compound [Na].C=1C=CC=CC=1C(=O)C1=CC=CC=C1 AASUFOVSZUIILF-UHFFFAOYSA-N 0.000 description 22
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 21
- 239000008346 aqueous phase Substances 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 19
- 239000013078 crystal Substances 0.000 description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 0 CC1(*)CN(C)CC(C)(*)CCC1 Chemical compound CC1(*)CN(C)CC(C)(*)CCC1 0.000 description 15
- 239000000872 buffer Substances 0.000 description 15
- VBLVGORCSZWNOH-UHFFFAOYSA-N 2,2,6,6-tetramethyl-[1,3]dioxolo[4,5-f][1,3]benzodioxole Chemical compound C1=C2OC(C)(C)OC2=CC2=C1OC(C)(C)O2 VBLVGORCSZWNOH-UHFFFAOYSA-N 0.000 description 14
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 13
- 230000001965 increasing effect Effects 0.000 description 13
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 13
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 13
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 230000008020 evaporation Effects 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 238000003384 imaging method Methods 0.000 description 11
- 150000002576 ketones Chemical class 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 229910006124 SOCl2 Inorganic materials 0.000 description 9
- 239000005864 Sulphur Substances 0.000 description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 229940093499 ethyl acetate Drugs 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 229910000162 sodium phosphate Inorganic materials 0.000 description 9
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 8
- 150000001768 cations Chemical class 0.000 description 8
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 8
- 238000001990 intravenous administration Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 229910052725 zinc Inorganic materials 0.000 description 8
- 125000005605 benzo group Chemical class 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 229910052593 corundum Inorganic materials 0.000 description 7
- 238000001362 electron spin resonance spectrum Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- MCZDHTKJGDCTAE-UHFFFAOYSA-M tetrabutylazanium;acetate Chemical compound CC([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC MCZDHTKJGDCTAE-UHFFFAOYSA-M 0.000 description 7
- 229910001845 yogo sapphire Inorganic materials 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- UYQMSQMCIYSXOW-UHFFFAOYSA-N benzene-1,2,4,5-tetrol Chemical compound OC1=CC(O)=C(O)C=C1O UYQMSQMCIYSXOW-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 5
- 239000001110 calcium chloride Substances 0.000 description 5
- 229910001628 calcium chloride Inorganic materials 0.000 description 5
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- 230000003197 catalytic effect Effects 0.000 description 5
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- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
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- 239000012043 crude product Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
- 229910003002 lithium salt Inorganic materials 0.000 description 5
- 159000000002 lithium salts Chemical class 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- 229930192474 thiophene Natural products 0.000 description 5
- QFSYADJLNBHAKO-UHFFFAOYSA-N 2,5-dihydroxy-1,4-benzoquinone Chemical compound OC1=CC(=O)C(O)=CC1=O QFSYADJLNBHAKO-UHFFFAOYSA-N 0.000 description 4
- RWMUCWSCZCYSIU-UHFFFAOYSA-N 4-bromothieno[3,4-d][1,3]dioxole-6-carboxylic acid Chemical compound O1COC2=C(C(=O)O)SC(Br)=C21 RWMUCWSCZCYSIU-UHFFFAOYSA-N 0.000 description 4
- 229910021554 Chromium(II) chloride Inorganic materials 0.000 description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 229910004878 Na2S2O4 Inorganic materials 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 4
- 235000010323 ascorbic acid Nutrition 0.000 description 4
- 229960005070 ascorbic acid Drugs 0.000 description 4
- 239000011668 ascorbic acid Substances 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 4
- 239000000428 dust Substances 0.000 description 4
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 4
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- 238000005829 trimerization reaction Methods 0.000 description 1
- LRZITUQPCGBEOD-UHFFFAOYSA-N trimethyl-[2,4,5-tris(trimethylsilyloxy)phenoxy]silane Chemical compound C[Si](C)(C)OC1=CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C=C1O[Si](C)(C)C LRZITUQPCGBEOD-UHFFFAOYSA-N 0.000 description 1
- ZUBSMWVVIFQTJD-UHFFFAOYSA-N tris(1-benzothiophen-2-yl)methanol Chemical compound C1=CC=C2SC(C(C=3SC4=CC=CC=C4C=3)(C=3SC4=CC=CC=C4C=3)O)=CC2=C1 ZUBSMWVVIFQTJD-UHFFFAOYSA-N 0.000 description 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 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K49/20—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations containing free radicals, e.g. trityl radical for overhauser
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to the use of stable free radicals, in particular inert carbon radicals, as image enhancing agents in magnetic resonance imaging (MRI) as well as to contrast media containing such radicals and to the use of such radicals and their non- radical precursors in the manufacture of MRI contrast media.
- MRI magnetic resonance imaging
- MRI is a diagnostic technique that has become particularly attractive to physicians as it is non- invasive and does not involve exposing the patient under study to potentially harmful radiation, such as for example the X-radiation of conventional radiography.
- MR images are generated by manipulation of the MR signals detected from the sample, for example a human or animal body, placed in a magnetic field and exposed to pulses of radiation of a frequency (typically
- radiofrequency (RF) selected to excite MR transitions in selected non-zero spin nuclei (the "imaging nuclei", which are generally water protons in body fluids) in the sample.
- the amplitude of the induced MR signals is
- the strength of the magnetic field experienced by the sample dependent upon various factors such as the strength of the magnetic field experienced by the sample, the temperature of the sample, the density of the imaging nuclei within the sample, the isotopic nature and chemical environment of the imaging nuclei and the local inhomogeneities in magnetic field experienced by the imaging nuclei.
- enhancing MR image quality for example by increasing MR signal amplitude or by increasing the difference in MR signal amplitude between different tissue types.
- the imaging parameters may be altered and many
- MRI contrast agents are paramagnetic they produce significant reduction in the T 1 of the water protons in the body zones into which they are administered or at which they congregate, and where the materials are ferromagnetic or superparamagnetic (for example as suggested by Jacobsen) they produce a significant reduction in the T 2 of the water protons. In either case the result is enhanced (positive or negative) contrast in the MR images of such zones.
- contrast enhancement achievable by such agents in conventional MRI is relatively limited and it is generally not such as to allow a reduction in the image acquisition period or in the field strength of the primary magnet.
- This new technique for generating a MR image of the sample which is hereinafter termed electron spin resonance enhanced magnetic resonance imaging (ESREMRI), or Overhauser MRI, involves exposing the sample to a first radiation of a frequency selected to excite nuclear spin transitions in selected nuclei in the sample (radiation which is generally of radiofrequency or thereabouts and thus for convenience will be referred to hereinafter as RF radiation) and also exposing the sample to a second radiation of a frequency selected to excite electron spin transitions coupled to nuclear spin transitions for at least some of the selected nuclei (radiation which is generally of microwave frequency or thereabouts and thus for convenience is referred to hereinafter as MW or UHF radiation), the MR images being generated from the resulting amplified MR signals (free induction decay signals) emitted by the sample.
- RF radiation radiofrequency or thereabouts and thus for convenience will be referred to hereinafter as RF radiation
- MW or UHF radiation the MR images being generated from the resulting amplified MR signals (free
- the paramagnetic substance which possesses the ESR transition which couples with the NMR transition of the image nuclei may be naturally present within the imaging sample or more usually may be administered as an ESREMRI contrast agent.
- Hafslund Nycomed Innovation AB proposed the use of deuterated stable free radicals, in particular deuterated nitroxide stable free radicals, as ESREMRI contrast agents.
- Organic free radicals however frequently have properties which render them unsuitable for use as
- ESREMRI contrast agents Thus free radicals commonly are unstable in physiological conditions, or have very short half-lives leading to toxicity problems. A further drawback is the low relaxivity exhibited by many free radicals, which results in poor coupling of the electron and nuclear spin transitions and thus a poor enhancement of the magnetic resonance signal. A need therefore exists for improved free radical ESREMRI contrast agents.
- the ESREMRI contrast agents so far proposed in the literature have all been "oxygen free radicals" that is to say radicals where the unpaired electron or electrons are associated with oxygen atoms.
- free radicals For such free radicals to be effective, they should be relatively long lived and to distinguish from free radicals which have a momentary existence, those usable as ESREMRI contrast agents will be referred to herein as being "inert" free radicals, that is having a half life of at least one minute at ambient temperature.
- the present invention thus provides the use of an inert carbon free radical for the manufacture of a contrast medium for use in ESREMRI.
- the invention also provides a method of magnetic resonance investigation of a sample, said method comprising introducing into said sample an inert carbon free radical, exposing said sample to a first radiation of a frequency selected to excite electron spin transitions in said free radical, exposing said sample to a second radiation of a
- the invention also provides a magnetic resonance imaging contrast medium comprising a physiologically tolerable inert carbon free radical together with at least one
- the inert carbon free radical should of course preferably be a physiologically
- tolerable radical or one presented in a physiologically tolerable, e.g. encapsulated, form.
- Inert carbon free radicals are well known and a renge of these has been described for example by
- Preferred inert carbon free radicals for use according to the invention exhibit high stability to oxygen, to pH, for example in the range pH 5-9, and in aqueous solution, particularly stability up to a
- dimerization long half-life, preferably greater than 1 minute, particularly preferably greater than 1 hour and especially preferably 1 year, long relaxation times, both T 1e and T 2e preferably being greater than 1 ⁇ sec, high relaxivity, for example greater than 0.3 mM -1 sec -1 and a small number of esr transition lines.
- Particularly preferred inert carbon free radicals include the substituted methyl radicals, in particular triarylmethyl radicals where each of the three aromatic substituent groups may be the same or different and where two or three such groups may optionally be linked together.
- Particularly preferably the radical comprises optionally substituted six-membered carbocyclic or heterocyclic aromatic rings optionally carrying one or more fused carbocyclic or heterocyclic rings.
- aromatic rings of the triarylmethyl radical advantageously are substituted and the nuclear identities of nuclei in all substituents and their position within the molecule should be selected so as to minimise their effect (line splitting or broadening) on the esr transition.
- a six-membered aromatic ring is preferably substituted at the ortho and para positions. This is desirable in order to minimise dimerisation and oxygen attack on the molecule.
- the meta position is optionally substituted, preferably with a bulky
- substituents again to minimise attack by oxygen and at least one of the substituents should conveniently comprise a water solubilizing moiety.
- substituents preferably have no magnetic moment, or have a very low effective spin density.
- Particularly preferred inert carbon free radicals include the triarylmethyl radicals of formula I
- radicals include those of formula la
- each Ar 12 which may be the same or different, comprises an optionally substituted 5-7 membered
- carbocyclic or heterocyclic aromatic ring optionally carying one or more fused carbocyclic or heterocyclic rings, one or more such Ar 12 groups preferably being a group Ar 1 as defined herein.
- each group Ar 1 represents a 6 membered carbon-attached carbocyclic or heterocyclic aromatic ring containing up to 2 non-adjacent ring nitrogens optionally substituted at the or any ortho carbon by a group R 1 to R 4 , at the or any meta carbon by a group R 2 or R 3 and at any para carbon by a group
- R 1 ,R 2 ,R 3 or R 4 with the proviso that no more than two ring carbons are unsubstituted, preferably only one ring carbon at most being unsubstituted;
- each of R 1 to R 4 which may be the same or different, independently represents a group of formula -M, -XM,
- M represents a water solubilizing group, each group X, which may be the same or different, represents an oxygen or sulphur atom or a NH or CH 2 group;
- Ar 2 represents a 5 to 10 membered aromatic ring
- R 5 represents a hydrogen atom or an optionally hydroxylated, optionally aminated
- R 2 and R 3 may also represent hydrogen atoms or alkyl groups
- R 1 , R 2 , R 3 or R 4 preferably groups at the ortho and meta portions, together with the two intervening carbon atoms may represent groups of formula
- R 6 represents a hydrogen atom, a hydroxyl group, an optionally alkoxylated, optionally hydroxylated acyloxy or alkyl group or a solubilising group M;
- Z represents an oxygen or sulphur atom or a group NR 5 , CR 7 2 , or SiR 7 2 ;
- each R 7 which may be the same or different, represents a hydrogen atom, an alkyl, hydroxyalkyl, alkoxycarbonyl or carbamoyl group or two groups R 7 together with the atom to which they are bound represent a carbonyl group or a 5 to 8 membered cycloalkylidene, mono- or di- oxacycloalkylidene, mono- or di-azacycloalkylidene or mono- or di-thiacycloalkylidene group optionally with the ring attachment carbon replaced by a silicon atom (preferably however in any spiro structure the ring linking atom will be bonded to no more than
- the groups Ar 1 are preferably groups of formula
- each Y independently represents CH, or more preferably CM, C-XM, C-Ar 2 , C-XAr 2 or a nitrogen atom.
- radicals of formula I are new and they, their salts and their non-radical precursors (i.e, compounds of formula (Ar 12 ) 3 CX 4 or (Ar 1 ) 3 CX 4 where X 4 is a leaving group, e.g. hydrogen, hydroxyl, halogen,
- the solubilizing groups M may be any of the solubilizing groups conventionally used in diagnostic and
- solubilizing groups M include optionally hydroxylated, optionally alkoxylated alkyl or oxo-alkyl groups and groups of formulae R 5 , COOR 5 , OCOR 5 , CHO, CN, CH 2 S(O)R 5 , CONR 5 2 , NR 5 COR 5 , NR 5 2 , SO 2 NR 5 2 , OR 5 , PO 3 2- , SOR 5 , SO 2 R 5 , SO 3 M 1 , COOM 1 (where M 1 is one equivalent of a physiologically tolerable cation, for example an alkali or alkaline earth metal cation, an ammonium ion or an organic amine cation, for example a meglumine ion), -(O(CH 2 ) n ) m OR 5 (where n is an integer having a value of from 1 to 3 and m is an integer having a value of from 1 to 5),
- R 10 is a group R 5 or an alkyl group
- solubilizing groups M are groups of formula C(H) 3-n (CH 2 OH) n , R 9 , COR 9 , SR 9 , SOR 9 ,
- R 9 group attached to a sulphur, nitrogen or oxygen atom is preferably not hydroxylated at the ⁇ carbon
- groups of formula SR 12 where R 12 is a group CH 2 COOR 13 , CH(COOR 13 ) 2 , CH 2 CONHR 9 , CH 2 CONR 9 2 ,
- solubilising groups M or XM include groups of formula X' C((CH 2 ) n COOR 13 ) 2 R 14 , X'C((CH 2 ) n COOR 13 ) 3 and X'C((CH 2 ) n COOR 13 )R 14 2 , where R 13 is as defined above, n is an integer from 1 to 3, X' is an oxygen or sulphur atom, and R 14 is a hydroxyalkyl group such as a group R 9 as earlier defined.
- R 1 groups include for example the following structures
- n 1 is 0, 1 or 2 and R 19 is hydrogen or C 1-4 alkyl
- R 23 is C 1-4 alkyl (e.g.
- NR 2 21 or OR 21 and R 21 is C 1-4 alkyl
- M represents a group containing a moiety NR 5 2
- this may also represent an optionally substituted nitrogen-attached 5 to 7 membered heterocyclic ring optionally containing at least one further ring
- heteroatom e.g. N or O, for example a group of formula
- any alkyl or alkenyl moiety conveniently will contain up to 6, especially up to 4, carbon atoms and any aryl moiety will preferably contain 5 to 7 ring atoms in the or any aromatic ring and especially preferably will comprise an aromatic ring with 0, 1 or 2 further aromatic rings fused directly or indirectly thereto.
- Preferred structures for the aryl substituents on the carbon radical centre include those in which at least one of such substituents carries at least one, and preferably two, fused rings of formula
- X is oxygen or sulphur and R 7 is hydrogen or optionally hydroxylated methyl.
- X oxygen or sulphur
- Y is N
- CCOOR 5 CSR 5 , CM or C-XM and M
- R 5 and Z are as earlier defined.
- Particularly preferred structures include those in which CR 7 2 represents CH 2 , C(CH 2 OH) 2 or C(CH 3 ) 2 , X
- R 1 is a group M or XM as hereinbefore defined and M 2 represents a solubilising group M or a group SCH 3 , S(O)CH 3 , S(O 2 )CH 3 , SCH 2 CH 2 N(CH 3 ) 2 , SCH 2 COOH, SCH 2 COOCH 3 , SCH 2 COOCH 2 CH 3 and SC(H) 3-n (CH 2 OH) n where n is an integer of from 1 to 3.
- Ar 1 include optionally substituted benzo [1,2-d:4,5-d']bis[1,3]dioxole, benzo[1,2-d:4,5-d']bis[1,3]dithiole, and benzo[1,2- d:4,5-d']bis[1,3]oxathiole groups.
- Preferred inert carbon free radicals for use according to the invention include the following:
- Especially preferred inert cation free radicals include
- R 42 , R 43 and R 44 are non-ionic solubilising groups e.g. hydroxyalkyl or alkoxyalkyl groups
- Inert free radicals which have relatively few transitions, e.g. less than 15, preferably less than 10, in their ESR spectra and radicals having narrow
- linewidth ESR transitions e.g. up to 500 mG, preferably less than 150 mG, especially less than 60 mG and
- ESREMRI contrast agents particularly less than 25mG, are especially preferred for use as ESREMRI contrast agents.
- the linewidths referred to are conveniently the intrinsic linewidths (full width at half maximum in the absorption spectrum) at ambient conditions).
- triarylmethyl free radicals of formula I are themselves novel and in a further aspect the present invention also provides novel inert carbon free radicals of formula I or salts thereof.
- contrast agents generally be considered for use as contrast agents.
- triaryl methyl radicals are water- insoluble and are therefore generally not suited for administration to the body.
- the choice of triaryl methyl radicals as ESREMRI contrast agents is therefore not an obvious one.
- novel triarylmethyl radicals of the invention include radicals which surprisingly are stable at physiological pH, have long half lives (at least one minute, and preferably at least one hour), long
- Water-soluble triaryl methyl radicals are a particularly important aspect of the invention.
- the triarylmethyl radicals may be coupled to further molecules for example to lipophilic moieties such as long chain fatty acids or to macromolecules, such as polymers, proteins, polysaccharides (e.g.
- the macromolecule may be a tissue-specific biomolecule such as an antibody or a backbone polymer such as polylysine capable of carrying a number of independent radical groups which may itself be attached to a further tissue-specific biomolecule such as an antibody or a backbone polymer such as polylysine capable of carrying a number of independent radical groups which may itself be attached to a further tissue-specific biomolecule such as an antibody or a backbone polymer such as polylysine capable of carrying a number of independent radical groups which may itself be attached to a further
- novel triarylmethyl radicals of the invention may also be used as ESR spin labels in ESR imaging or in magnetometry.
- the inert carbon free radicals may be prepared from their non-radical precursor compounds by conventional radical generation methods.
- Suitable non-radical precursor compounds include the corresponding triaryl methanes, triaryl methyl halides and triaryl methanols, and derivatives, e.g. ethers, of the triaryl methanols.
- the invention provides a process for the preparation of the novel triarylmethyl radicals of the invention which comprises subjecting a radical precursor therefor to a redical generation step and optionally subsequently modifying the substitution on the aryl moieties, e.g. by oxidation or reduction.
- a radical precursor therefor e.g. -SCH 3 or -SCH 2 COOEt
- sulphide substituents e.g. -SCH 3 or -SCH 2 COOEt
- lipophilic substituents such as -SCH 2 COOEt
- hydrophilic substituents such as -SCH 2 COOEt
- radical-precursor can be represented by formula XXXV
- corresponding triaryl methyl halides by reduction with a metal catalyst, such as copper, zinc or silver, or by electrolytic reaction on an electrode or by photochemical reaction in the presence of a chlorine radical scavenger, e.g. an olefin.
- a chlorine radical scavenger e.g. an olefin.
- carbon free radicals may be prepared from the corresponding triaryl methanes by reaction with a base, e.g. in the presence of sodium hydride followed by a reaction with an oxidant, e.g. iodine in the presence of oxygen or a quinone such as chloranil, following for example the method described in US-A-3347941.
- triarylmethyl radicals Another method to prepare triarylmethyl radicals is to react triarylmethanes with other, less stable radicals such as tert-butoxyl radicals.
- the latter radicals are generated in situ via thermolysis or photolysis of an appropriate precursor, such as a peroxide or an azo compound.
- a further example of a method by which radical preparation may be effected is reaction of the corresponding triaryl methanols in the presence of an acid to form a carbonium ion followed by reduction to the free radical in the presence of a suitable reducing agent, such as metal ions e.g. Cr 2+ , Fe 2+ , or by electrochemical reduction.
- the carbon free radicals may also be generated by a comproportionation reaction between cations and anions of a corresponding radical precursor. In such a reaction an electron is exchanged between the anion and the cation, and two radicals are generated.
- Triarylmethyl radicals may thus be prepared by mixing together a triarylmethyl radical precursor
- Triarylmethyl radicals may also be prepared by
- thermolysis or photolysis or a corresponding dimeric triarylmethyl structure for example an
- radicals with long half lives in aqueous solution for example at least one hour, preferably ten days, more preferably fifty days and especially
- At least one year are clearly particularly desirable for use in in vivo imaging, shorter lived inert free radicals may still be utilised in imaging (e.g. of inanimate samples) and these may particularly conveniently be prepared immediately pre-administration.
- non-radical precursors may themselves be prepared by methods conventional in the art.
- a process for the preparation of a triaryl methyl radical precursor may comprise one or more of the following steps:- a) (to prepare a triarylmethanol of Formula II
- the starting ketone of formula XXVII may be prepared by oxidation, e.g. with CrO 3 , of the corresponding alcohol (Ar 12 ) 2 CHOH (itself preparable by reaction of the monoaldehyde Ar 12 CHO with an Ar 12 containing organometallic, e.g. Ar 12 Li or
- Ar 12 MgHal a compound formed by reaction of such an organometallic with the corresponding carboxylic acid Ar 12 COOH, or by reaction of the acid chloride Ar 12 COCl with Ar 12 H, e.g. in the presence of AlCl 3 .
- the starting material of formula XXXIV may be prepared by reaction of a
- step (g) may be effected using borane or LiAlH 4 and AlCl 3 .
- Triaryl methyl halides may be prepared following the procedures described by Dünnebacke et al. in Chem. Ber. 122:533-535 (1989).
- the substituents may be introduced onto individual Ar 12 groups before they are trimerized to form the triaryl radical precursor compounds, or they may be introduced directly onto the triaryl precursor compound or the actual radical itself. It is also possible to effect the substitution and trimerization steps
- the Ar 12 groups may be prepared by following:
- R 7 ' is a hydrogen atom or a group R 7 as hereinbefore defined, optionally protected by a protecting group.
- reaction schemes such as the following may be used
- R 1 ' to R 4 ' are optionally protected groups R 1 to R 4 and R 5 is as hereinbefore defined.
- R 1 ' and R 2 ' and R 3 ' and R 4 ' may represent ring-forming groups -X-CR 7 ' 2 -X-, e.g. OC(CH 3 ) 2 O-.
- a particularly interesting group of radicals for use according to the invention includes compounds of Formula .C(Ar 12 ) 3 , where one, two or three Ar 12 groups comprises a central 5-6 membered carbocyclic or heterocyclic aromatic ring bearing two five-membered fused rings, each said fused ring
- the "monomer” and “dimer” compounds, having this structure are particularly useful for the preparation of the radical precursors and thus in a further aspect the invention provides tricylic compound comprising a central 5-6 membered carbocyclic or heterocyclic
- Particularly preferred embodiments of such compounds are the compounds of formula XL
- Y 1 is a group CH, N, CCOOR 5 , CSR 5 , CM or CXM, R 5 and M are as defined in claim 6 and R 40 is a hydrogen atom, or a optionally substituted hydroxyl, methyl or formyl group or group
- Particularly preferred compounds of formula XL include those wherein each X is oxygen, each R 7 is optionally hydroxylated methyl and Y 1 is other than N.
- the invention also provides, in another aspect, process for the preparation of a compound of formula XL, said process comprising condensing a compound of formula XLI
- R 40 ' and Y'' are groups R 40 or Y 1 as defined in claim 23 or protected such groups, and X is as defined in claim 23
- a compound of formula (R 7 ') 2 CX where R 7 ' is a group R 7 as defined in claim 23 or a protected R 7 group
- contrast media for use in ESREMRI, the inert carbon free radicals are conveniently formulated into contrast media together with conventional pharmaceutical carriers or excipients.
- Contrast media manufactured or used according to this invention may contain, besides the inert free radicals (or the non-radical precursor where radical formation is to be effected immediately before administration), formulation aids such as are conventional for
- the media may for example include solubilizing agents, emulsifiers, viscosity enhancers, buffers, etc.
- the media may be in forms suitable for parenteral (e.g. intravenous) or enteral (e.g. oral) application, for example for application directly into body cavities having external voidance ducts (such as the gastrointestinal tract, the bladder and the uterus), or for injection or infusion into the cardiovascular system.
- parenteral e.g. intravenous
- enteral e.g. oral
- solutions, suspensions and dispersions in physiological tolerable media will generally be preferred.
- Free radicals which are relatively unstable or insoluble in the sample environment may be encapsulated, e.g. in gastric juice resistant capsules containing a medium in which they are stable.
- the radical may be presented as an encapsulated freeze dried powder in a soluble capsule. Such formulations might conveniently be dissolved shortly before in vivo use.
- the medium which preferably will be substantially isotonic, may conveniently be administered at a concentration
- concentration of the free radical in the imaging zone is a balance between various factors. In general, optimum concentrations would in most cases lie in the range 0.1 to 100mM, especially 0.2 to 10mM, more especially 0.5 to 5mM.
- Compositions for intravenous administration would preferably contain the free radical in concentrations of 10 to 1000mM
- the concentration will particularly preferably be in the range 50 to 200mM, especially 130 to 170mM and for non- ionic materials 200 to 400mM, especially 290 to 330mM.
- compositions may perhaps be used having concentrations of for example 10 to 100mM for ionic or 20 to 200mM for non-ionic materials.
- concentration may conveniently be 0.1 to 100mM, preferably 5 to 25mM, especially preferably 6 to 15mM.
- the image was acquired under the following
- TR 0.5 sec
- UHF Irradiation Time 0.38 sec
- 256 excitations 256 x 256 matrix).
- Slice thickness 1 cm.
- Field of view 25 cm.90° flip angle (SR).
- the UHF-resonator had a very low loaded Q ⁇ 10 (200 g rat), and a volume of approximately 1L (diameter 10 cm).
- the applied UHF power was ⁇ 30 W of which only a small fraction was deposited in the animal ( ⁇ 1/10).
- the proton coil had a diameter of 126 cm and thus a very low filling factor when loaded, with a rat (5 cm).
- the Q factor of this coil was high (> 1000), but loaded with both UHF-resonator and animal decreased to below 500.
- the signal/noise (S/N) ratio was approximately 100.
- the perorlly applied volume of contrast medium was approximately 5ml and the concentration of radical was less than 05mM.
- Ammonia was condensed (ca 200ml) into 150 ml of dry diethylether in a 3-necked flask, with external cooling. Then 9.0 g (0.0256 mole) of 2,5-dibenzylmercapto-p- benzoquinone was dissolved into the liquid. Sodium (5.9 g, 0.256 mole) cut into fine pieces was added portionwise with efficient stirring. After stirring for an additional 2.5 hours, abs. ethanol (20 ml) was added and the ammonia was evaporated. Water (170 ml) was added to the reaction product and it was extracted with 2 x 30 ml of ether. The aqueous phase was then
- 1,3,5,7-Tetrathia-S-indacene-2,6-dione (4.0 g, 0.016 mole, prepared according to Larsen and Bechgaard J. Org Chem 52 : 3287 (1987)) was suspended in 60 ml of a IM solution of sodium methoxide in methanol. Stirring was maintained for 1/2 hour at ambient temp, until a clear solution was formed. The reaction mixture was then evaporated to dryness and the residue acidified with 5 N hydrochloric acid to pH 1. The aqueous phase was extracted with 3 x 70 ml of methylene chloride. The organic phases were dried (Na 2 SO 4 ), the solvent
- the corresponding radical showed a linewidth of 500 mG in its ESR spectrum and an Overhauser enhancement of 8 at 5hr UHF power.
- Tris-(3-methylthio-2,2,6,6-tetramethylbenzo[1,2- d:4,5-d']bis(1,3)dioxole)methanol (0.3 mmol. Example 7) was dissolved in 50 ml dry THF (Al 2 O 3 , super I, basic) under Argon. 0.5 g CrCl 2 and then 0.5 ml BF 3 etherate was added to the vigorously stirred mixture. After 15 minutes the reaction mixture was poured over 50 ml 4 M NaOH. The organic phase was separated and filtered through a short column of SiO 2 and eluted with dry ether. The dark violet solution was evaporated to dryness yielding 176 mg (71%) of the title compound as a black powder. A solution of this material in tetrahydrofuran was shown to contain 41% radical according to the method of Evans (J. Chem. Soc. 2003 (1959)).
- reaction mixture was left to stand with stirring at ambient temperature for an additional 30 minutes. After cooling to -78°C, 2.5ml BuLi 2.5m) was added. After stirring for 1 hour at room temperature a white, thin, slurry had formed. It was cooled to 78°C and 0.81 ml diethylcarbonate was added slowly. The mixture was left to stir at ambient temperature and the white suspension thickened and changed colour from yellow to brown. After 1.5 hours the reaction mixture was poured into 100 ml diethylether with about 30g NaH 2 PO 4 saturated with N 2 . The phases were separated and the H 2 O-phase was extracted once with 100 ml diethylether.
- Tris (8-formyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis (1,3)dioxole-4-yl)methanol (1.26 g, 1.62 mmol (prepared by reaction of tris(2,2,6,6-tetramethylbenzo[l,2-d:4,5- d']bis(1,3)dioxol-4-yl)methanol (See Example 44) with nBuLi in DMF) ) was dissolved in dry MeOH (80 mL). To this solution was added MnO 2 (18.9 g, 217 mmol), NaCN (1.26 g, 25.7 mmol) and acetic acid (HOAc) (1.26 mL).
- the reaction mixture was heated to 65 °C for 40 h and was then filtered through Celite and the filtrate was evaporated to dryness.
- the residue was partitioned between CH 2 Cl 2 (100 mL) and water (40 mL).
- the organic phase was washed with another 2x30 mL of water, the organic phase was separated, dried (Na 2 SO 4 ) and the solvent was evaporated to yield a yellow to brown residue, which was further pumped to dryness.
- the residual foam was chromatographed on a column packed with SiO 2 , eluting with CH 2 Cl 2 /Et 2 O (4:1). The fractions containing pure product were collected and the solvent was evaporated to yield 1.1 g (77 %) of pure
- aromatic C-O aromatic C-O
- 118.2 alifatic O-C-O
- 111.9 quart. C-subst. aromatic
- 105.9 quart. p-C-subst. aromatic
- 72.1 quart, alifatic C-OH
- 24.6 CH 3
- Trimethylsilyl chloride (68.1 mL, 539 mmol) and sodium iodide (81.0 g, 540 mmol) were mixed in acetonitrile (500 mL), and tris (2,2,6,6-tetramethylbenzo[1,2-d:
- Tris (2,2,6,6-tetramethyl-benzo[1,2-d:4,5-d']bis (1,3)- dioxole-4-yl)methane (1.65 g, 0.244 mmol.
- Example 17 was dissolved in dry diethyl ether (150 mL).
- n-BuLi (5.86 mL, 2.5 M in toluene, 1.465 mmol) was added in two portions (2/3 and 1/3), and the temperature of the mixture was raised to 40 °C (the ether refluxed). After maintaining this temp, for 15-20 min, the mixture was poured onto CO 2 (s), and left overnight. Water (90 mL) was added to dissolve the solid residue.
- Tris(2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)- dioxole-4-yl)methane (3.00 g, 4.40 -mmol (Example 17)) was dissolved in ether (100 mL) and n-BuLi (10.8 mL, 27.0 mmol) was added. The mixture was refluxed for 20 min, and after cooling to room temperature
- Tris (2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)- dioxole-4-yl)methane (1.35 g, 2.0 mmol (Example 17)) was dissolved in dry THF (400 mL) under N 2 , and the temp was lowered to -40 °C and n-BuLi (4.86 mL, 12.2 mmol) was added and the temperature was allowed to rise gradually to 0°C. The mixture was cooled to -60 °C, and a
- Acetic anhydride (AcO) 2 O (30 mL) was added to pyridine (35 mL).
- Tris(8-hydroxymethyl-2,2,6,6-tetramethylbenzo [1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)methanol (0.400 g, 0.51 mmol (Example 33) was added under stirring, which was maintained at room temperature for two days.
- Tris(2,2,6,6-tetramethyl-benzo[1,2-d:4,5-d']-bis(1,3)-di oxole-4-yl) methane (2.0 g, 3.5 mmol (Example 17) was dissolved in dry ether (100 mL) at room temperature.
- n-butyl lithium (6 mL) was added, and the reaction mixture was heated to reflux (15 min). At this temperature another portion of n-butyl lithium (2 mL) was added and the heating was
- Tris(8-formyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis (1,3)-dioxole-4-yl)methane (140 mg, 0.18 mmol.
- Example 23 was dissolved in a mixture of dry DMSO (15 mL) and of dry ether (50 mL). NaH (5 mg, 0.19 mmol) and t-BuOK (catalytic amount) were added under N 2 -atmosphere. The color of the solution changed from yellow to deep green-blue. After 4h of stirring at room temperature under N 2 I 2 (46 mg, 0.18 mmol) was added, and after 2 min the reaction mixture was poured into a saturated
- ESR 4 lines (internal ratio 1:3:3:1) with line widths of ca 70 mG.
- Tris(8-formyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis (1,3)dioxole-4-yl)methanol 200 mg, 0.20 mmol was dissolved in of dry THF (15 mL) and SOCl 2 (80 mg, 0.20 mmol) was added. After stirring at room temperature for 2 h the solvent was evaporated ( ⁇ 70 °C) and the residue was pumped dry overnight. The orange product
- N 2 -atmosphere was added; first SnCl 2 (0.15 g, 0.80 mmol) and then Zn(Hg), (0.15 g, 2.20 mmol) (prepared by treating 120 g zinc powder with a mixture of 12g HgCl 2 , 6 mL cone. HCl and 150 mL of water for 5 min. and decanting off the liquid). Stirring was maintained for 0.5 h. The reaction mixture was applied to a column (1 cm diameter) consisting of 3 cm of SiO 2 at the bottom and 15 cm of Chelex 100 on top. Elution was performed with dry THF under N 2 -atmosphere. The eluent was evaporated to dryness, leaving a brown-black crystalline residue (0.19 g, 100%).
- Tris(8-methoxycarbonyl-2,2,6,6-tetramethylbenzo[1,2-d:4, 5-d']-bis(1,3)dioxol-4-yl)methanol 240 mg.
- Example 15 was dissolved in of dry THF (25 mL) and SOCl2 (38 mg, 23 'L) was added at room temperature. Stirring was maintained for 2.5 h. The solvent of the reaction mixture was then evaporated to dryness ( ⁇ 70 °C).
- a radical content of ca 5% was estimated by ESR.
- the Overhauser enhancement was 80.
- n-butyllithium (4.25 mL, 10.6 mmol) was added.
- the dry ice/acetone bath was exchanged with a water/ice bath.
- the new cooling bath was removed after one hour and forty five minutes.
- Cold (-78 °C) diethylcarbonate (0.363 mL, 3 mmol) in THF (10 mL) was cannulated into the reaction mixture over a period of 10 minutes.
- the resulting mixture was kept at (-70) - (-78) °C for two hours, followed by a period of one hour and thirty minutes at approximately 0 °C (ice/water bath).
- the mixture was then stirred till noon the following day without addition of ice, at which time the temperature inside the reaction flask was +16 °C.
- the mixture was then stirred without external cooling for three more hours, poured into a half saturated sodium
- Tris(8-mercapto-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-b is (1,3)dioxol-4-yl)methanol (2.93 g, 50%, 1.86 mmol) was dissolved in dry DMF (100 mL) under argon. K 2 CO 3 (4 g) was added and the solution cooled to the freezing point. Ethylchloroacetate (5 mL, 46.7 mmol, Janssen 11822.85) was added, and the reaction mixture was stirred at room temperature overnight. Most of the DMF and excess ethylchloroacetate were removed by high vacuum distillation at 30-40 °C.
- UV (Absorbt ion maxima/minima) 195 (p) , 229 (sh) , 302 (v) ,
- ESR 7 lines, lw 30 mG, aH 60 mG.
- Tris(8-ethoxycarbonylmethylthio-2,2,6,6,- tetramethylbenzo-[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl) methyl (1.97 g, 1.91 mmol 90 % pure) was dissolved in a degassed (helium followed by argon) mixture of dioxane (Lab Scan C2512 HPLC quality) and water (200 mL (3:1)).
- Sodium hydroxide (4.3 mL, 2 M, 8.58 mmol, He, Ar, 0 °C) was added and the hydrolysis performed in a ultrasound bath (Sonorex RK 2555). The reaction was followed by HPLC, RP18 column (Nucleosil 5 mm) with
- the detector system consisted of a diode array UV detector - Varian 9065 polychrome). During the reaction the diester- and monoester radicals were observed as well as the tricarboxylic acid salts. The reaction mixture was frozen when the HPLC analysis showed pure tricarboxylic acid sodium salt (mixture of radical and carbinol) and subjected to freeze drying.
- ESR H 2 O 0.3 mM, 200 G: 7 lines, Lw 27 mG, a 60 mG,
- alkaline water was added (150 mL, 1 M, degassed with argon) followed by vigorous stirring in ten minutes. The phases were separated and the water phase was washed with diethylether (100 mL, degassed with argon). The water phase was acidified with HCl (5 M). The
- diethylether 50 mL, argon
- organic phases were combined, washed (sodium dihydrogen phosphate buffer, 30 mL), dried (MgSO 4 , 30 min) and evaporated to dryness.
- Diethylether dry, argon was added to the brown oil to induce the crystallization. Upon the dissolution of the oil the title compound crystallized as porous yellow crystals. The product was isolated by filtration.
- Tris(2,2,6,6-tetramethylbenzo([1,2-d:4,5-d']-bis(1,3)- dioxol-4-yl)methanol (6.35 g, 9.38 mmol) was dissolved in dry diethylether (200 mL) under argon and cooled to 0°C.
- n-Butyllithium (22.5 mL, 56.30.10-3 mol) was added and the temperature was increased to induce reflux. The reaction mixture was refluxed for 25 minutes. After cooling to 0 °C, dry formaldehyde (gas, formed by
- Tin(II) chloride (127 mg, 0.986 mmol) was added 10 minutes after the boron compound, and zinc (187 mg, 2.85 mmol) was added after another 15 minutes. One hour and fifteen minutes later the reaction mixture was green. The solution was evaporated, and subsequently filtered through a SiO 2 column with tetrahydrofuran as the eluent. The residue (80 mg, 0.099 mmol, 87% (containing some radical precur) was dissolved in tetrahydrofuran and the radical characterized by ESR and Overhauser
- reaction mixture was evaporated and checked with 13 C NMR without removing the excess diethanol amine from the intermediary tris(8-di(hydroxyethyl)- aminocarbonylmethylthio-2,2,6,6-tetramethylbenzo[1,2-d: 4,5-d']-bis(1,3)dioxole-4-yl)methanol: [(CD 3 OD, 75 MHz) ⁇ : 171.34, 142.55, 139.97, 119.12, 112.99, 98.94, 60.73, 60.58, 52.97, 50.36, 36.84, 25.88, central COH at ca.
- Tris(8-ethoxycarbonylmethylthio-2,2,6,6-tetramethylbenzo -[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)methanol (4.00 g, 3.819 mmol (Example 27)) was dissolved/suspended in a mixture of water and ethanol (200 mL, (1:1)) and cooled to approximately 5°C.
- Sodium hydroxide (15.3 mL, 1.0 M, 15.3 mmol) was added and the reaction was followed by HPLC. The next day more sodium hydroxide (3.82 mL, 1.0 M, 3.82 mmol) and (7.64 mL, 1.0 M, 7.64 mmol) was added.
- the ethanol was evaporated after complete conversion had been observed (HPLC).
- the alkaline aqueous phase was extracted with heptane (2x100 mL) and then acidified with HCl (2.0 M) to pH 5.
- the product was taken up in diethylether (2x100 mL). Upon further acidification of the aqueous phase (to pH 3), more precipitate was formed. This was also taken up in diethylether (2x100 mL).
- the combined ether phases were extracted once with water (100 mL) and dried (Na 2 SO 4 ). Evaporation yielded 3.11 g (3.23 mmol, 85 %) of a white crystalline material. When the material was dried at very high vacuum and high temperature the substance turned blue, possibly due to the formation of an internal zwitter ion. Upon exposure to moist air the white color
- reaction mixture was poured into a solution of NaOH (50 mL, IM) and extracted with diethyl ether (100 mL).
- the aqueous phase was acidified with cone. HCl to pH 2 while stirring.
- the product was isolated by extracting with diethyl ether (3x50 mL).
- Tris(8-ethoxycarbonylmethylthio-2,2,6,6-tetramethylbenzo [1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)methanol (1.06 g, 1.01 mmol (Example 27) was added to a solution of trimethyl silylchloride (0,767 mL, 6.07 mmol) and sodium iodide (0.91 g, 6.07 mmol) in acetonitrile (50 mL) and stirred for ten minutes. Saturated sodium thiosulfate (30 mL) was added, followed by diethylether (70 mL), and the mixture was stirred for 10 minutes.
- the phases were separated and the organic phase was washed with water (30 mL).
- the organic phase was diluted with more ether (100 mL), since crystals had started to form in the funnel.
- the solution wds kept in the freezer over night after drying (MgSO 4 ) and filtration.
- the crystals formed were removed (impurity) and the solution evaporated to dryness.
- the product was purified by dissolving the substance at room temperature in diispropyl ether (E. Merck 118867, 30 mL), followed by bubbling with helium.
- the flask was stoppered and put in the refrigerator for two and a half hours.
- the product was collected by filtration (glass sinter no. 3), and the mother liquor was evaporated to approximately half the volume.
- the total yield after collecting the second crop was 640 mg
- Tris(8-mercapto-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-b is (1,3)dioxole-4-yl)methanol (1.00 g, 1.27 mmol
- Tris(8-mercapto-2,2,6,6-tetramethylbenzo[1,2-d:4,5- d']bis(1,3)dioxole-4-yl)methanol 1.000 g, 1.269 mmol Example 31 was added to a solution of acetonitrile (75 mL, argon bubbled) and potassium carbonate (6.0 g).
- Tris(8-ethyloxycarbonylthio-2,2,6,6- tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole-4- yl)methanol (0.100 g, 0.099 mmol.
- Example 45 was dissolved in THF (5 mL, sodium benzophenone ketyl) and SOCl 2 (0.073 mL, 0.998 mmol) was added. The mixture was stirred for 3 hours and then evaporated under argon.
- Overhauser enhancements (THF, 548.9 MHz, 200 G) : 9 mW 12 enhancement, 18 mW 25 enhancement.
- Tris(8-mercapto-2,2,6,6-tetramethylbenzo[1,2-d:4,5- d']bis(1,3)dioxole-4-yl)methanol 1.000 g, 1.268 mmol.
- Example 31 pyridine (0.620 mL, 7.606 mmol) and N,N- dimethylamino-pyridine (catalytic amount) were added to degassed (argon bubbled) acetonitrile (50 mL) and cooled close to the freezing point.
- 2,2-Dimethylpropanoic acid chloride 0.40 mL, 7.606 mmol
- Tris(8-tertbutylcarbonylthio-2,2,6,6- tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole-4- yl)methanol (0.0957 g, 0.0919 mmol.
- Example 47 was dissolved in THF (25 mL, argon atmosphere., potassium benzophenone ketyl dried), and BF 3 .OEt 2 (0.5 mL, 48% in diethyl ether, Fluka) was added. After stirring for 5 minutes SnCl 2 (0.1249 g, 0.659 mmol) was added followed by a gradual change in color to light brown.
- Zinc (0.5 g, 7.646 mmol) was added 1.5 hours after the SnCl 2 . Two hours later the color had changed to green. A sample taken (after letting the Zn settle) with a gas tight syringe showed a large Overhauser enhancement.
- the reaction mixture was poured onto a column consisting of three layers; top layer SiO 2 , intermediate layer SiO 2 and K 2 CO 3 1:1 and bottom layer SiO 2 .
- the K 2 CO 3 binds the BF 3 .OEt 2 , which has to be removed to avoid destabilizing the corresponding cation radicals. Yield: 0.079 g
- ESR (THF, 200 G) : Linewidth 109 mG, one unresolved line.
- Overhauser enhancements (THF, 548.9 MHz, 200 G, conc. ⁇ 1 mM) : 9 mW 96 enhancement, 18 mW 114 enhancement.
- Tris(8-mercapto-2,2,6,6-tetramethylbenzo[1,2-d:4,5- d']bis(1,3)dioxole-4-yl)methanol 1.000 g, 1.268 mmol, Example 31
- acetyl chloride 0.540 mL, 7.605 mmol
- K 2 CO 3 2.0 g, 1.447 mmol
- Tris(8-methylcarbonylthio-2,2,6,6-tetramethylbenzo[1,2- d:4,5-d']bis(1,3)dioxole-4-yl)methanol (0.0915 g, 0.0999 mmol, Example 49) was dissolved in THF (25 mL, argon atmosphere, potassium benzophenone ketyl dried), and BF 3 .OEt 2 (0.5 mL, 48% in diethyl ether Fluka) was added. A temporary red color was seen when the drops were hitting the surface of the solution. After stirring for 5 minutes, SnCl 2 (0.1249 g, 0.659 mmol) was added
- 1,2,4,5-Tetrahydroxybenzene (5.00 g, 35.00 mmol, Example 4) was dissolved in THF (200 mL) and cyclohexanone (13.0 mL, 140.00 mmol) was added in one portion. P 2 O 5 was then added in small portions under efficient stirring. After addition was completed the temperature was increased to 80 °C for 4 hours. One large ball was formed in the flask during this time. After cooling to room
- Benzo[1,2-d:4,5-d']bis(1,3)dioxole-2,6- dispirocyclohexane (2.00 g, 6.60 mmol, Example 52) was dissolved in diethyl ether (80 ml, dried over Al 2 O 3 ) and cooled to -10 °C in an ice acetone bath.
- n-Butyl lithium (3.70 mL, 2.5 M in hexane) was added with a syringe over a period of five minutes. The mixture was stirred at the same temperature for 1 hour and overnight at room temperature. Diethyl carbonate (0.28 mL, 2.4 mmol) was added at room temperature and the mixture immediately changed color to red-brown.
- 2,5-Dihydroxy-1,4-benzoquinone (4.00 g, 28.55 mmol) was suspended in water (50 ml, distilled) followed by Na 2 S 2 O 4 (10.00 g, 57.47 mmol) and HCl (5.5 g, 55.75 mmol cone, soln.). The mixture was stirred 30 min. at room temperature
- 2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole (8.80 g, 40.00 mmol. Example 5) was dissolved in THF (100 mL) and cooled to -20 °C. n-Butyllithium (25.0 mL, 40.0 mmol, 1.6 M) was added and the temperature was adjusted to ambient temperature over a period of 30 minutes and then recooled to -20 °C.
- Example 51 was dissolved in a CH 3 CN (50 mL) and cooled to 0 °C. CH 3 I (0.42 ml, 6.74 mmol) and K 2 CO 3 (4.0 g) were added. The resulting mixture was stirred at room temperature for 70 minutes. Before filtering away the
- Tris(8-tertbutylcarbonylthio-2,2,6,6- tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole-4- yl)methane (0.205 g, 0.200 mmol, 97.3 %).
- ESR 200 G, 548.9 MHz, three lines, THF: Linewidth 85 mG, a H 175 mG.
- Tris(8-formyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis- (1,3)dioxole-4-yl)methane (0.104 g, 0.134 mmol, Example 23) was dissolved in a mixture of DMSO (10 mL), and diethyl ether (30 mL). NaH (0.0037 g, 0.134 mmol, 80% in oil) and KOtBu (catalytic amount) were added and the resulting mixture was stirred under argon. Samples (about 50 mL) were taken with irregular intervals and quenched with DCl/D 2 O (10% DCl) under argon. After 2 hours and 15 min. the 1 H NMR measurements of the
- the mixture was diluted with diethyl ether (50 mL) and washed with Na 2 S 2 O 3 (sat. 2x25 mL), dried (Na 2 SO 4 ) and evaporated yielding 0.030 g (40.8%).
- the radical content was 60 % according to 1 H NMR (Evans method) and 64% by HPLC (Kromasil 10 mm, C8, 250 mm long, i.d. 4.6 mm, CH 3 CN:H 2 O 70:30 to 100:0 gradient 20 minutes, UV 254 nm detection).
- the HPLC chromatogram of the tris(8-formyl-2,2,6,6- tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole-4- yl)methyl radical showed a peak at 5.93 s corresponding to the radical and a peak at 6.58 s corresponding to the starting material.
- the HPLC separated materials also showed distinct UV spectra.
- the white crystals were washed with diethyl ether (50 mL, sodium benzophenone ketyl) under argon, and the ether removed by filtration through the sinter. Weighing of the flask with the dry lithium salt indicated that there remained around 8 mmol lithium salt in the flask. THF (70 mL) was added to the salt, the mixture cooled to 0 °C, and diethyl carbonate (0.654 mL, 5.4 mmol) was cannulated into the solution and the mixture was left overnight to reach room temperature.
- Tris(2-methoxycarbonylthien-4-yl)methane (0.218 g, 0.5 mmol. Example 66) was dissolved in dry THF (25 ml) under an argon atmosphere. Solid KOtBu (0.055 g, 0.5 mmol) was added, the solution was stirred for 30 min. and I 2 (0.127 g, 1.0 mmol) was added.
- Tris(8-methylthio-2,2,6,6-tetramethylbenzo[1,2-d:4,5- d']-bis(1,3)dioxole-4-yl)methyl (0.163 g, 0.20 mmol. approximately 15 % radical content, Example 8) was dissolved in CH 2 Cl 2 (10 ml) under an argon atmosphere and 3-chloroperbenzoic acid (0.207 g, 1.20 mmol) was added. After stirring for 15 minutes, ESR spectroscopy of the reaction mixture showed a new radical.
- ESR 6 lines with a H : 290 mG, linewidth: 113 mG.
- Chelex-100 was treated with 14 g (of SnCl 2 .H 2 O, 116 mequiv.) in water (100 mL). The solid material was filtered and washed with water (100 mL) and EtOH (500 mL) and ether (100 mL) and was then dried in a
- Example 4 was dispersed, in pyridine (100 mL) and diethyl ether (100 mL), and Me 3 SiCl (70 mL, 645 mmol) was slowly added (heat evolved). After 3 hours the pyridiniumchloride was filtered off and the solvents of the filtrate (red) were evaporated, leaving a red oil, which was dissolved in ether, more solid material was filtered off, and the solvents of the filtrate (red) were evaporated. The residue was dissolved in diethyl ether and extracted with water (2x50 mL).
- Tris(8-nitromethylhydroxymethyl-2,2,6,6- tetramethylbenzo-[1,2-d:4,5-d']bis(1,3)dioxole-4- yl)methane (0.670 g, 0.710 mmol (Example 83)) was dissolved in Ac 2 O (30 mL) and NaOAc (2.00 g, 24.4 mmol) was added and the reaction mixture was refluxed for 0.5 h. The solution turned deep red. The solvent was
- 3,4-Methylenedioxy-2,5-thiophenedicarboxylic acid diethylester (3.08 g, 11.3 mmol (Example 75)) was refluxed in EtOH/KOH (88 mL EtOH and 5.57 g, 11.3 mmol KOH) for 48 h.
- EtOH/KOH 88 mL EtOH and 5.57 g, 11.3 mmol KOH
- the reaction mixture was allowed to cool and the precipitate was filtered and the filter cake was triturated with cold 0.1 M HCl.
- the basic filtrate from the first filtration was also triturated with 0.1 M HCl and the crystals from these acidifications were pooled, dried and later recrystallized from water/EtOH (1:1) and yielded 2.62 g (95%) of the desired mono-carboxylic acid.
- Example 80 The product of Example 80 (0.100 g, 0.370 mmol) was dissolved in CH 2 Cl 2 and chilled to 0 °C and molecular sieves (3 ⁇ , dried at 350 °C in vacuum) were added before adding SOCl 2 (740 mmol). The reaction mixture was stirred at room temperature over night. Excess solvent and SOCl 2 were removed under reduced pressure and the residue was partitioned between 10% Na 2 CO 3 and CH 2 Cl 2 . The organic phase was separated, dried (Na 2 SO 4 ), filtered and the solvent was evaporated yielding 0.050 g (44%) of the desired product.
- Tris(8-formyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis- (1,3)dioxole-4-yl)methane (0.150 g, 0.197 mmol, Example 23) and nitromethane (0.36 g, 5.9 mmol) were mixed in dry dioxane (20 mL), and NaH (0.030 g, 0.197 mmol, 80 % in oil) was added at ambient temperature. After stirring overnight, the reaction was checked by TLC, and found to be completed. IR (film on NaCl) of the reaction mixture confirmed this, no CHO fragment coud be detected. Water (50 mL) and a few drops of HCl (2 M) were added.
- the mixture was extracted with ether (3x50 mL). The organic extracts were washed with water (40 mL), dried (Na 2 SO 4 ) and the solvent was evaporated, leaving a crystalline yellow residue.
- the product was chromatographed on a column of silica with CH 2 Cl 2 ,EtOAc 45:5 as eluent. The fractions containing pure product were pooled and the solvent was evaporated, yielding 0.150 g (81 %).
- Tris(8-diethylaminocarbonyl-2,2,6,6- tetramethylbenzo[1,2-d:4,5-d']bis-(1,3)dioxole-4- yl)methane (0.076 g, 0.080 mmol (Example 87)) was dissolved in a mixture of of dry THF (40 mL, sodium benzophenone ketyl) and dry DMSO (10 mL, molecular sieves 4 ⁇ ) under N 2 .
- KOtBu (0.009 g, 0.080 mmol) was added and the mixture stirred at room temperature for 4 hours.
- Tris(benzo[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methanol (1.00 g, 1.90 mmol (Example 3) was mixed with dry THF (25 mL, sodium benzophenone ketyl) under Ar (g) and cooled to -78 °C.
- n-BuLi (3.8 mL, 2.5 M solution in hexane) was added with a syringe. The cooling bath was removed and the resulting mixture was allowed to reach room temperature.
- the mixture turned thick and pasty and THF (25 mL, sodium benzophenone ketyl) was added in order to facilitate stirring.
- CH 3 SSCH 3 (1 mL) was added. The mixture became homogeneous (and dark) almost instantaneously.
- the reaction mixture was poured on ice-water (200 mL) and extracted with CH 2 Cl 2 (3x100 mL). The organic phase was dried
- Tris(8-methylthiobenzo[1,2-d:4,5-d']bis(1,3)dioxole-4- yl)methanol was converted to the corresponding radical with BF 3 .OEt 3 (cation formation) and CrCl 2 (reductant) as described in other Examples.
- the ESR spectrum showed a linewidth of 120 mG in THF at a concentration of 1 mM.
- the Overhauser enhancement was 10 at 5 W.
- Tris(8-formyl-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis- (1,3)dioxole-4-yl)methyl (0.065 g, 0.976 mmol (Example 64)), with a radical content of about 10%, and Na 2 S 2 O 5 (0.370 g, 1.95 mmol) were mixed in a 25 mL round flask under N 2 (g). Water (1.5 mL, He degassed 15 min.) and dioxane (1.5 mL, He degassed 15 min.) were added. After 15 minutes stirring most of the solid material had dissolved. HPLC analysis showed that the starting aldehyde was consumed after 45 minutes. An Overhauser experiment confirmed the presence of radical in the reaction mixture. Overhauser enhancement was 59 at 5W microwave power. ESR four lines, Linewidth 133 mG, a H 973 mG.
- the bisulfite adduct was precipitated by the addition of dioxane and the precipitate was filtered and washed twice with dioxane. The product was dried under vacuum in room temperature overnight.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU72350/91A AU651570B2 (en) | 1990-02-12 | 1991-02-12 | Triarylmethyl radicals and the use of inert carbon free radicals in MRI |
US07/916,974 US5599522A (en) | 1899-02-12 | 1991-02-12 | Triarylmethyl radicals and the use of inert carbon free radicals in MRI |
EP91903934A EP0515458B1 (en) | 1990-02-12 | 1991-02-12 | Triarylmethyl radicals and the use of inert carbon free radicals in mri |
DE69112384T DE69112384T2 (en) | 1990-02-12 | 1991-02-12 | TRIARYL METHYL RADICALS AND THE USE OF INERT CARBON-FREE RADICALS IN MRI. |
FI923589A FI923589A (en) | 1990-02-12 | 1992-08-11 | TRIARYLMETHYLRADIKALER OCH ANVAENDNING AV INERTA FRIA KOLRADIKALER I MRI. |
NO92923117A NO923117L (en) | 1990-02-12 | 1992-08-11 | TRIARYLRADICALS AND THE USE OF INERT FREE CARBON RADICALS |
GR950403056T GR3017947T3 (en) | 1990-02-12 | 1995-11-01 | Triarylmethyl radicals and the use of inert carbon free radicals in mri. |
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GB9003105.5 | 1990-02-12 | ||
GB909003105A GB9003105D0 (en) | 1990-02-12 | 1990-02-12 | Compositions |
GB9012300.1 | 1990-06-01 | ||
GB909012300A GB9012300D0 (en) | 1990-06-01 | 1990-06-01 | Compositions |
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WO1991012024A1 true WO1991012024A1 (en) | 1991-08-22 |
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PCT/EP1991/000285 WO1991012024A1 (en) | 1899-02-12 | 1991-02-12 | Triarylmethyl radicals and the use of inert carbon free radicals in mri |
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US (2) | US5599522A (en) |
EP (1) | EP0515458B1 (en) |
JP (1) | JP3175940B2 (en) |
AT (1) | ATE126707T1 (en) |
AU (1) | AU651570B2 (en) |
CA (1) | CA2075818A1 (en) |
DE (1) | DE69112384T2 (en) |
DK (1) | DK0515458T3 (en) |
ES (1) | ES2076522T3 (en) |
FI (1) | FI923589A (en) |
GR (1) | GR3017947T3 (en) |
IE (1) | IE69365B1 (en) |
NO (1) | NO923117L (en) |
WO (1) | WO1991012024A1 (en) |
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Also Published As
Publication number | Publication date |
---|---|
EP0515458B1 (en) | 1995-08-23 |
IE69365B1 (en) | 1996-09-04 |
FI923589A0 (en) | 1992-08-11 |
ATE126707T1 (en) | 1995-09-15 |
US5827501A (en) | 1998-10-27 |
CA2075818A1 (en) | 1991-08-13 |
AU7235091A (en) | 1991-09-03 |
JP3175940B2 (en) | 2001-06-11 |
NO923117L (en) | 1992-10-08 |
DE69112384D1 (en) | 1995-09-28 |
IE910462A1 (en) | 1991-08-14 |
DK0515458T3 (en) | 1995-09-25 |
NO923117D0 (en) | 1992-08-11 |
AU651570B2 (en) | 1994-07-28 |
DE69112384T2 (en) | 1996-03-28 |
ES2076522T3 (en) | 1995-11-01 |
JPH05506428A (en) | 1993-09-22 |
FI923589A (en) | 1992-08-11 |
US5599522A (en) | 1997-02-04 |
GR3017947T3 (en) | 1996-02-29 |
EP0515458A1 (en) | 1992-12-02 |
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