CN1152914A - Technetium-sulphonamide complexes, their use, pharmaceutical agents containing them, and process for producing the complexes and agents - Google Patents
Technetium-sulphonamide complexes, their use, pharmaceutical agents containing them, and process for producing the complexes and agents Download PDFInfo
- Publication number
- CN1152914A CN1152914A CN95194028A CN95194028A CN1152914A CN 1152914 A CN1152914 A CN 1152914A CN 95194028 A CN95194028 A CN 95194028A CN 95194028 A CN95194028 A CN 95194028A CN 1152914 A CN1152914 A CN 1152914A
- Authority
- CN
- China
- Prior art keywords
- group
- yield
- solution
- measured value
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title abstract description 19
- 230000008569 process Effects 0.000 title abstract description 3
- 239000008177 pharmaceutical agent Substances 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 239000000126 substance Substances 0.000 claims abstract description 17
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 13
- -1 imino, succinimido Chemical group 0.000 claims description 104
- 238000002360 preparation method Methods 0.000 claims description 45
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 29
- 229910052751 metal Inorganic materials 0.000 claims description 29
- 239000002184 metal Substances 0.000 claims description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 229910021645 metal ion Inorganic materials 0.000 claims description 22
- 239000002585 base Substances 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 229910052713 technetium Inorganic materials 0.000 claims description 9
- 125000000524 functional group Chemical group 0.000 claims description 7
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 108091033319 polynucleotide Proteins 0.000 claims description 6
- 102000040430 polynucleotide Human genes 0.000 claims description 6
- 239000002157 polynucleotide Substances 0.000 claims description 6
- 230000002285 radioactive effect Effects 0.000 claims description 6
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 230000003637 steroidlike Effects 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 229910044991 metal oxide Inorganic materials 0.000 claims description 3
- 150000004706 metal oxides Chemical class 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 3
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 230000000155 isotopic effect Effects 0.000 claims description 2
- 239000010936 titanium Substances 0.000 claims description 2
- 229910052719 titanium Inorganic materials 0.000 claims description 2
- 238000012546 transfer Methods 0.000 claims description 2
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 claims 1
- 229910052776 Thorium Inorganic materials 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 239000012736 aqueous medium Substances 0.000 claims 1
- 239000012141 concentrate Substances 0.000 abstract description 38
- 238000003745 diagnosis Methods 0.000 abstract description 5
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 4
- 239000013522 chelant Substances 0.000 abstract 1
- 125000000565 sulfonamide group Chemical group 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 292
- 239000000243 solution Substances 0.000 description 153
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 106
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- 238000003756 stirring Methods 0.000 description 72
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 238000010898 silica gel chromatography Methods 0.000 description 47
- 238000005406 washing Methods 0.000 description 45
- 239000012074 organic phase Substances 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 150000001408 amides Chemical class 0.000 description 40
- 239000007787 solid Substances 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- 238000000605 extraction Methods 0.000 description 28
- 238000001914 filtration Methods 0.000 description 28
- 238000010992 reflux Methods 0.000 description 28
- 238000010025 steaming Methods 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 26
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- 238000001035 drying Methods 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 23
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 23
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 21
- 238000001953 recrystallisation Methods 0.000 description 21
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 20
- 150000001538 azepines Chemical class 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- 150000001412 amines Chemical class 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 238000005984 hydrogenation reaction Methods 0.000 description 12
- 239000012217 radiopharmaceutical Substances 0.000 description 12
- 229940121896 radiopharmaceutical Drugs 0.000 description 12
- 230000002799 radiopharmaceutical effect Effects 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 238000007738 vacuum evaporation Methods 0.000 description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 11
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 11
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 238000001556 precipitation Methods 0.000 description 11
- 229940056501 technetium 99m Drugs 0.000 description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 10
- 235000017550 sodium carbonate Nutrition 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 9
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000003352 sequestering agent Substances 0.000 description 8
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- AXDLCFOOGCNDST-UHFFFAOYSA-N N-methyl-DL-tyrosine Natural products CNC(C(O)=O)CC1=CC=C(O)C=C1 AXDLCFOOGCNDST-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- MWZPENIJLUWBSY-VIFPVBQESA-N methyl L-tyrosinate Chemical compound COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MWZPENIJLUWBSY-VIFPVBQESA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 235000015320 potassium carbonate Nutrition 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 230000009918 complex formation Effects 0.000 description 6
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical group 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 6
- 229930182817 methionine Natural products 0.000 description 6
- 238000009206 nuclear medicine Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 6
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 6
- 229960004441 tyrosine Drugs 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- 229940022663 acetate Drugs 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical compound SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 5
- 238000005336 cracking Methods 0.000 description 5
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 5
- 229950006191 gluconic acid Drugs 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 229960005235 piperonyl butoxide Drugs 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 description 4
- 229940099500 cystamine Drugs 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- 235000011150 stannous chloride Nutrition 0.000 description 4
- 238000007070 tosylation reaction Methods 0.000 description 4
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 4
- 229940038773 trisodium citrate Drugs 0.000 description 4
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 3
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 3
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 description 3
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 239000001119 stannous chloride Substances 0.000 description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- ANOOTOPTCJRUPK-UHFFFAOYSA-N 1-iodohexane Chemical compound CCCCCCI ANOOTOPTCJRUPK-UHFFFAOYSA-N 0.000 description 2
- JDRMYOQETPMYQX-UHFFFAOYSA-M 4-methoxy-4-oxobutanoate Chemical compound COC(=O)CCC([O-])=O JDRMYOQETPMYQX-UHFFFAOYSA-M 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 101100208721 Mus musculus Usp5 gene Proteins 0.000 description 2
- NMOJAXCSURVGEY-UHFFFAOYSA-N N#CC#N.[S] Chemical compound N#CC#N.[S] NMOJAXCSURVGEY-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000007098 aminolysis reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- PWCONBNHBCCZHP-UHFFFAOYSA-N benzyl acetate hydrobromide Chemical compound Br.CC(=O)OCC1=CC=CC=C1 PWCONBNHBCCZHP-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- JDRMYOQETPMYQX-UHFFFAOYSA-N butanedioic acid monomethyl ester Natural products COC(=O)CCC(O)=O JDRMYOQETPMYQX-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 235000019628 coolness Nutrition 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229940021171 curative drug Drugs 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- SDJHDRMYZQFJJO-UHFFFAOYSA-N ethanethioic s-acid;potassium Chemical compound [K].CC(S)=O SDJHDRMYZQFJJO-UHFFFAOYSA-N 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 230000003760 hair shine Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- GRHBQAYDJPGGLF-UHFFFAOYSA-N isothiocyanic acid Chemical compound N=C=S GRHBQAYDJPGGLF-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910052702 rhenium Inorganic materials 0.000 description 2
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 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 2
- YXTDAZMTQFUZHK-ZVGUSBNCSA-L (2r,3r)-2,3-dihydroxybutanedioate;tin(2+) Chemical compound [Sn+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O YXTDAZMTQFUZHK-ZVGUSBNCSA-L 0.000 description 1
- FUFUQQWIXMPZFU-VIFPVBQESA-N (s)-methyl 2-amino-3-(4-nitrophenyl)propanoate Chemical compound COC(=O)[C@@H](N)CC1=CC=C([N+]([O-])=O)C=C1 FUFUQQWIXMPZFU-VIFPVBQESA-N 0.000 description 1
- JEJLGIQLPYYGEE-UHFFFAOYSA-N 1,2-dipalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCC JEJLGIQLPYYGEE-UHFFFAOYSA-N 0.000 description 1
- CLWAXFZCVYJLLM-UHFFFAOYSA-N 1-chlorohexadecane Chemical compound CCCCCCCCCCCCCCCCCl CLWAXFZCVYJLLM-UHFFFAOYSA-N 0.000 description 1
- GCDPERPXPREHJF-UHFFFAOYSA-N 1-iodododecane Chemical compound CCCCCCCCCCCCI GCDPERPXPREHJF-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- PRRSFMGODMUPJN-CABZTGNLSA-N 2-fluoro-4-[(2r,3s)-5,5,5-trifluoro-3-(3-fluoro-4-hydroxyphenyl)pentan-2-yl]phenol Chemical compound C1([C@@H](CC(F)(F)F)[C@@H](C)C=2C=C(F)C(O)=CC=2)=CC=C(O)C(F)=C1 PRRSFMGODMUPJN-CABZTGNLSA-N 0.000 description 1
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 description 1
- JWZFROYOPUCAEF-UHFFFAOYSA-N 2-sulfanyl-2-sulfanylideneacetic acid Chemical compound OC(=O)C(S)=S JWZFROYOPUCAEF-UHFFFAOYSA-N 0.000 description 1
- ZAGWQJWRWKULDE-UHFFFAOYSA-N 3,3,3-trifluoropropanethioic s-acid Chemical compound OC(=S)CC(F)(F)F ZAGWQJWRWKULDE-UHFFFAOYSA-N 0.000 description 1
- HVYWMOMLDIMFJA-UHFFFAOYSA-N 3-cholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 HVYWMOMLDIMFJA-UHFFFAOYSA-N 0.000 description 1
- MWWNNNAOGWPTQY-UHFFFAOYSA-N 3-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC(S(Cl)(=O)=O)=C1 MWWNNNAOGWPTQY-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- HCXJFMDOHDNDCC-UHFFFAOYSA-N 5-$l^{1}-oxidanyl-3,4-dihydropyrrol-2-one Chemical group O=C1CCC(=O)[N]1 HCXJFMDOHDNDCC-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000009007 Diagnostic Kit Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- RNZDACWUXZHQMI-CRQOXBRUSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] 4-methylbenzenesulfonate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)S(=O)(=O)C1=CC=C(C)C=C1 RNZDACWUXZHQMI-CRQOXBRUSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- JCXGWMGPZLAOME-AKLPVKDBSA-N bismuth-212 Chemical compound [212Bi] JCXGWMGPZLAOME-AKLPVKDBSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- OVIISSOUXFJLSM-KPNWGBFJSA-N butanedioic acid;(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical compound OC(=O)CCC(O)=O.C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 OVIISSOUXFJLSM-KPNWGBFJSA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940046044 combinations of antineoplastic agent Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004900 laundering Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000001483 mobilizing effect Effects 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- KDLHZDBZIXYQEI-AKLPVKDBSA-N palladium-109 Chemical compound [109Pd] KDLHZDBZIXYQEI-AKLPVKDBSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229950009730 pentafluranol Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical group [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 238000002602 scintillography Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229940007163 stannous tartrate Drugs 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003495 technetium Chemical class 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-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
- 238000012360 testing method Methods 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M thiocyanate group Chemical group [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- IUTCEZPPWBHGIX-UHFFFAOYSA-N tin(2+) Chemical class [Sn+2] IUTCEZPPWBHGIX-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-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
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/28—Isothiocyanates having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Optics & Photonics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to novel chelate formers containing sulphonamide groups and their metallic chelates of general formula (I) in which n, m, p, V<1>, V<2>, V<3>, V<4>, X<1>, X<2>, X<3>, R<1>, R<2>, R<3> and R<4> have different meanings, pharmaceutical agents containing these compounds, their use in X-ray diagnosis and therapy, processes for producing these compounds and agents, and conjugates of these compounds with substances which selectively concentrate themselves in diseased tissue, especially peptides.
Description
Medicament and the method for preparing these title complexs and medicament
The content that the present invention relates to illustrate in the claims, that is: contain sulfoamido new sequestrant, its metal complexes, contain these compounds medicament, be used for radiodiagnosis and radiocurable purposes, prepare the method for these compounds and medicament, and these compounds and selectivity is gathered in pathological tissue material, the especially binding substances of peptide class.
Radiopharmaceuticals is used to diagnose and treats is the field of biology and medical research for a long time.Radiopharmaceuticals is particularly useful for showing specific structure, for example bone, organ or tissue.The diagnostic prerequisite of radiopharmaceuticals is that after giving patient's medication, these radiopharmaceuticals accumulate in the weave construction that will check specifically.Utilize suitable detector then, for example scintiphotograph machine or other suitable production method are carried out tracing study, curves drawing or scintillography to the radioactive substance of these local accumulation.Distribution and the relative intensity of detected radiopharmaceuticals in human body can be found, thereby unusual, the pathologic that can demonstrate weave construction and function change or the like.Radiopharmaceuticals can be used as curative drug in a similar fashion, shines specific pathological tissues or zone.This methods of treatment need be prepared and can accumulate in ad hoc structure, tissue or intraorganic radiotherapy medicine.By gathering these medicines, can directly treat irradiation to pathological tissue.
Normally metal active nucleus as diagnostic medicine or curative drug; this metal exists as ion or with the metal complexes form with free form; the metal radioactive nuleus that for example can form title complex have technetium-99m; with the coordination thing of various rheniums, the former is as diagnosis, and the latter is used for the treatment of; radiopharmaceuticals is except that containing metal (title complex); usually also have appropriate carriers and additive, as physiologic buffer, salt etc., so that injection, suction or oral administration during the treatment patient.
The most frequently used active nucleus is technetium-99m in the field of nuclear medicine, and (no emblem grain shines, and the physiology transformation period is 6 hours because it has good physics characteristic, the 140KeVr-ray), and very little radiation exposure load is arranged, and therefore is radio isotope preferably, is suitable in vivo diagnosing.Technetium-99m is a no problem as nucleic generation source, thereby can this kind form be directly used in the conventional clinically diagnostic kit that needs of manufacturing.
At first need to synthesize suitable part during the preparation radiopharmaceuticals.When clinical need be used title complex, now was directly by complex-bound agent (back is called part or sequestrant) and required radionuclide preparation.For this reason, the complex-bound agent in the test kit that will deposit with lyophilized form is reacted under the condition that title complex generates with the solution that contains radionuclide.For example, under suitable condition, just generate corresponding technetium complexes if preparation technetium-99m radiopharmaceuticals is then added the part that makes reductive agent and added Pertechnetate solution.Then with mode such as injection, suction or oral the give patient of this title complex to suit.
The solution that contains radionuclide such as technetium-99m can be obtained by the commercially available Mo-99/Tc-99m nucleic source that contains.If perhaps during rhenium 186, directly obtain by manufactory.The title complex formation reaction is to finish in following several minutes of suitable temperature (as 20-100 ℃) or a few hours.For title complex is generated fully, need excessive adding part (greater than 100 times), complete for making reduction reaction, use the reductive agent of q.s (as SnCl
2, S
2O
4Deng).
Technetium has multiple oxidation state (+7～-1) usually, because of its title complex has different electric charges, can very big influence be arranged to pharmacological properties.So, require the preliminary sequestrant must stably technetium be combined in a certain predetermined oxidation state, to avoid taking place in vivo redox processes, technetium dissociates in the technetium diagnostic reagent again, take place this biological the dispersion in ground if things turn out contrary to one's wishes, is certain to make medical diagnosis on disease more difficult.
The effect of the radionuclide that is used in vivo to diagnose and treats depends on specificity and the selectivity of mark sequestrant to target cell.For improving this character, can inner complex be coupled on the biomacromolecule according to " targeted drug " principle.Biomolecules has antibody, antibody fragment, hormone, somatomedin, the substrates of acceptor and enzyme etc. are at UK Patent Application GB2,109, set forth in 407 be used for diagnosing tumor in vivo to the antigenic radioactivity traget antibody of antineoplastic combination, set forth in addition by with technetium-99m to the proteinic body gene (amino of giving, amido, sulfydryl etc.) directly carry out protein signization (Journal of Nuclear Medicine (J.Nukl.Med.) such as B.A.Rhodes, 1986,27:685-693), perhaps technetium-99m is introduced in the complex-bound agent (US4,479,930 and A.R.Fritzberg etc., Journal of Nuclear Medicine (J.Nuel Med.), 1986,27,957).Yet these experimental techniques are unsuitable for clinical application, because on the one hand its selectivity is too low, it is in the too high again and imaging in vivo of machine intravital " substrate activity " on the other hand.
The suitable title complex of technetium and rhenium isotope forms agent for example cyclammonium, as radioisotopic application ((Appl.Radiol.Isot) 1982 such as Von Volkert, 33:891) and Journal of Nuclear Medicine (J.Nucl.Med.) such as Troutmer, 1980,21:443 is described, but its shortcoming is: only in pH value＞9 o'clock, and could be preferably in conjunction with technetium-99m.
N
2O
2Though system can use clinically, its shortcoming is: this metal complexes less stable in vivo.According to the research of Pillai and Troutner, this title complex in blood plasma, can lose after 1 hour composition metal up to 30% (M.R.A.Pillai, D.E.Troutner etc.: inorganic chemistry (Inorg.Chem.) 1990,29:1850).
Non-annularity N
4The disadvantage of-system such as HM-PAO is that the stability of title complex is too low.Tc-99m-HM-PAO is because of its poor stability (J.R.Ballinger etc., radioisotopic application (Appl.Radiat.Isot.) 1991,42:315; M.W.Billinghurst etc., radioisotopic application (Appl.Radiat.1sot.) 1991,42:607) must be behind mark use in 30 minutes, could guarantee that like this it has only the degradation production of a small amount of, this degradation production has different pharmacokinetics and drainage properties.Such radiochemical impurity can increase the difficulty that diagnoses the illness.Do not have the method for simple possible these inner complexs or inner complex can be generated agent and be coupled on the material that other selectivity accumulates in intralesional, thereby they are non-specific distribution usually in body.
N
2S
2-sequestrant (G.Bormans etc., nuclear medicine biology (Nucl Med.Biol.) 1990,17:499) as inferior second dicysteine (A.M.Verbruggen etc., Journal of Nuclear Medicine (J.Nucl Med.) 1992, though 33:551) satisfied the stability requirement of technetium-99m title complex, but, just form purity greater than 69% radiodiagnosis agent only in complex media PH＞9 o'clock.
Hitherto known N
3(the A.Fritzburg of S-system; EP0173424 and EP0250013) though form stable technetium-99m title complex, when only being heated to about 100 ℃, just can obtain single this radiopharmaceuticals.
Wish day by day that in recent years radiodiagnosis agent can accumulate in pathological tissues specifically, be coupled to easily on the material that selectivity gathers, do not lose its good fiting property again simultaneously, then can reach this purpose if title complex forms agent.Owing to be coupled to the bad stability that can make title complex on such molecule owing to utilize title complex to form one of function in the agent through regular meeting; so so far the complex-bound agent being coupled to the work that selectivity gathers on the material still can not be satisfactory; when diagnosis; binding substances discharges the isotropic substance (M.W.Brechbiel etc. that can not tolerate in vivo; inorganic chemistry (Inorg.Chem.) 1986; 25; 2772); so need preparation bi-functional title complex to form agent; its existing functional group; can be in conjunction with required metal ion, another or a plurality of functional group are also arranged, to be incorporated on the material that selectivity gathers.Such double function ligand can be chemically bound in technetium or rhenium isotope specifically, they is coupled on the different biological substances, and also carries out so-called preliminary making.
Narrated some inner complexs and form agent in EP0247866,0188256 and 0200492, they can be coupled on monoclonal antibody or the lipid acid.Mention N as what inner complex formed agent
2S
2-system.Because of its low stability should not be used.Selectivity gather material because of in nature and the mechanism gathered very big difference is arranged, thereby to have the sequestrant of different coupling capacities to form agent, and can satisfy biological requirements such as the lipotropy of its coupling object and membrane permeability.
Thereby task of the present invention is, seeks title complex or title complex and forms agent, and they can overcome the defective on the prior art, that is:
-under physiology PH condition, can form agent and certain metal oxide (salt) is prepared by corresponding title complex;
-at a lower temperature, be preferable under the room temperature, can form agent and certain metal oxide/salt is prepared by corresponding title complex;
-in vivo under the condition, title complex also has very high stability;
-the very high selectivity and the specificity of tissue/organ arranged.
Therefore, this title complex should satisfy such requirement: promptly usually to the requirement of medicine, as good tolerability (promptly having no side effect), good solubleness and drainage are fully.
The invention solves this task.
Prove that compound of Formula I is suitable to especially preparation radiodiagnosis agent and radiotherapy dose
V in the formula
1, V
2, V
3And V
4Independent separately represent carbonyl,
Or-CH
2-Ji; X
1Represent hydrogen atom, the optional C that is replaced by a carboxyl, amino or thiocyano
1-C
12-alkyl or ordination number are 43,45,46,75, the metal ion Equivalent of 82 or 83 radioelement metal ion; X
2, X
3An independent separately metal ion Equivalent representing the radioelement metal ion of hydrogen atom or above-mentioned ordination number; N, m, p represent 0 or 1, m+n=1, R
1Represent hydrogen atom, carboxyl or-the U-Z base, U represents singly-bound, straight or branched, saturated or unsaturated C
1-C
20Alkyl, it is optional contains dimaleoyl imino, succinimido, optional by the phenyl of 1-5 fluorine atom, amino or nitro replacement, one or two imino-, phenylene, inferior phenoxy group, inferior phenylamino, amido, hydrazide group, carbonyl, urea groups, thioureido, thio acylamino, ester group, 1-2 Sauerstoffatom, sulphur atom and/or nitrogen-atoms, and optional 1-5 hydroxyl, sulfydryl, oxo, sulfo-, carboxyl, alkane carboxylic acid group, ester group, thiocyano and/or amino; Z represents hydrogen atom, the segment of amino acid, peptide, polynucleotide or steroidal compounds, or the optional functional group that can link to each other with amino acid, titanium, polynucleotide or steroidal thing; R
2Represent the C of straight or branched
1-C
10-alkyl, the optional carboxyl, C of containing on it
7-C
12-aralkyl, or aromatic nucleus can randomly be replaced by chlorine, bromine, thiocyano, methyl, ethyl, carboxyl and/or methoxyl group on it; R
4Represent hydrogen atom or carboxyl, or work as R
1During for hydrogen or carboxyl, then be-the U-Z base, the implication of U, Z is the same, R
3Be hydrogen atom, the metallic element ion Equivalent of aforementioned ordination number, trifluoroacetic acid base, acetoxyl, benzoyloxy, C
1-C
6-acyl group, benzoyl, glycolyl, ethanamide methyl, the optional benzoyloxy that is replaced by chlorine atom, bromine atoms or a methyl, ethyl, carboxyl and/or methoxyl group, to methoxybenzyl, ethoxyethyl, SH-protecting group,
Perhaps work as X
2, X
3Be hydrogen, X
1Be hydrogen or the optional C that replaces
1-C
12During alkyl, R
3Be formula II group
V in the formula
1, V
2, V
3, V
4, X
1, X
2, X
3, n, m, p, R
1, R
2And R
4Implication the same, V wherein
1, V
2, V
3, V
4In at least one, to too many by two be carbonyl.
Title complex of the present invention forms agent (sequestrant), is X in the general formula I
1, X
2, X
3And R
3For those compounds (but except metal ion Equivalent) of above-mentioned implication can satisfy aforesaid requirement.They especially have following feature: they can in physiological pH value and low temperature be rapid down and certain selected metal forms title complex, thereby is particularly suitable for routine clinical application.
In complex formation, by its R
3Implication be the elemental metals title complex that the sequestrant of the pulsating dimerization of general formula I I forms formula I, its R
3Implication be the metal ion Equivalent.
Ordination number is the radioactive metal ion of 43,45,46,75,82 or 83 element, radio isotope technetium-99m for example, rubidium-103, palladium-109, rhenium-186, plumbous-212 and bismuth 212 can be used as metal ion.The principle of selecting for use depends on required range of application.The present invention preferably uses the metal complexes of technetium and rhenium element.
General formula I title complex of the present invention then can be used for single photon emission imaging technique (SPECT) if contain the isotropic substance such as the Tc-99m that can launch the r-ray.
General formula I title complex of the present invention is if contain the isotropic substance such as the Bi-211 that can launch alpha particle, Bi-212, and Bi-213, isotropic substance such as the Re-186 or the Re-188 of Bi-214 or emission beta-rays then can be used for radiotherapy.
The preferred compound of the present invention is V among the formula I
1And V
4Be respectively carbonyl, V
2And V
3For-CH
2-Ji, P are those of zero.
R
1Base can be thought of as hydrogen or carboxyl, especially-the U-Z base, wherein Z is a hydrogen atom, but is preferably the segment with tissue or the specific biomolecules of structure, or with the functional group that the activation form exists, is connected by this biomolecules in case of necessity.The example of biomolecules has the segment of amino acid, peptide or steroidal, steroid hormone (male sex hormone, progestin, oestrogenic hormon, cholesterol, chlolic acid derivatives, progestogen or the like) as is known, and polynucleotide such as RNA or DNA.
The example of the functional group that can link to each other with biomolecules has :-COOH ,-SCN ,-OH, Cl or-NH
2, these functional groups also can exist as succinimide ester or acyl chlorides by its activated form.
U can be preferably strand, can be straight or branched, saturated or undersaturated C
1-C
20-alkyl, the optional succinimido that contains, contain the optional phenyl that is replaced by 1-5 fluorine atom, amino or nitro, contain one or two imino-s, phenylene, inferior phenoxy group, inferior phenylamino, amido, hydrazide group, carbonyl, urea groups, thioureido, thio acylamino, ester group, 1-2 oxygen, sulphur and/or nitrogen-atoms replace, and contain an optional 1-5 hydroxyl, sulfydryl, oxo, sulfo-, carboxyl, alkane carboxyl, ester group, thiocyanate groups and/or amino.
For example when Z was biomolecules, U was-CH
2-C
6H
4-O-CH
2-C
6H
4-,-CH
2-C
6H
4-O-CO-C
15H
30-,-CH
2-C
6H
4-O-CO-(CH
2)
2-COO-,-CH
2-C
6H
4-O-CH
2-COO-C
6H
4-NH-,-CH
2-C
6H
4-O-CH
2-COO-,-(CH
2)
5-COO-, or one-CH
2-C
6H
4-O-(CH
2)
2-O-(CH
2)
2-O--group
When Z was hydrogen ,-UZ was-CH
2-C
6H
4-O-CH
2-COO-C
6F
5,-CH
2-C
6H
4-O-CH
2-C
6H
5,-CH
2-C
6H
4-O-CH
3,-CH
2-C
6H
4-O-C
6H
3,-CH
2-C
6H
4-O-C
12H
25Or e-CH
2-C
6H
4-O-CO-C
15H
31When Z was the mobilizing function base of choosing wantonly ,-U-Z was :-CH
2-(CH
2)
4-NCS ,-CH
2-C
6H
4-O-CO-(CH
2)
2-COOH ,-CH
2-C
6H
4-O-CH
2-COO-C
6H
4-NH
2,-CH
2-C
6H
4-O-CH
2-COO-C
6H
4-NO
2,-CH
2-C
6H
4-NCS,
-CH
2-C
6H
4-O-(CH
2)
2-O-(CH
2)
2-OH or one-CH
2-C
6H
4-O-CH
2-COOH-group is that Z is-NCS ,-COOH ,-NH
2,-NO
2,-OH or one
R
2Base can be-C
6H
4-NCS-base or C
6H
4-COOH base, especially-CH
3Or phenyl ring.
R
3Representationally be: a) when forming agent for title complex, R
3For-the SH protecting group, as-COCH
3,
-COC
6H
5,-COCF
3Or-C (C
6H
5)
3Base, or the group of general formula I I, the V in the formula
1, V
2, V
3, V
4, X
1, X
2, X
3, n, m, p, R
1, R
2, R
4Implication the same; B) when being title complex of the present invention, R
3Be an aforesaid group, but the group of general formula I I exception, but R
3It also can be the metal ion Equivalent of radioactive metal ion of the element of aforementioned ordination number.
Title complex forms in the agent, X
2, X
3Be hydrogen atom, X
1Be hydrogen atom or the optional C that replaces
1-C
12Alkyl.And in the title complex, according to the oxidation state of metal wherein, X
1, X
2, X
3Or R
3In at least 2 be the metal ion Equivalent.
R
4Be hydrogen or carboxyl, but R
4Also can be-the U-Z base, U and Z have aforesaid implication, usually are R
1And R
4Maximum expression-U-Z-bases in two groups.The R of the preferred compound of the present invention
4Be hydrogen.
Coefficient m and n are numeral 0 or 1, because when title complex synthetic of the present invention forms agent, isomeric compound can occur, so m and n sum are always 1.
The invention still further relates to the preparation method of title complex formation agent and title complex, the reaction path that synthetic compound formation agent is adopted is had any different according to target structure is different.Narrate representational synthetic method below, other title complex forms agent and can be prepared according to being similar to described synthetic method.1. if will prepare R
1In contain-OC
6H
4-CH
2The part of-Ji then can be easily from tyrosine ester, method and reagent Z that its amino is at first known with the technician
1-Cl reaction, Z
1Be any one amino protecting group, be preferably carbobenzoxy-(Cbz) (being called the Z-yl later on).By currently known methods phenolic hydroxyl group and iodomethane reaction are carried out alkanisation then, but the amino protecting group acidic cleavage then for example carries out tosylation with toluene sulfonyl chloride.Intermediate product that obtains and reacting ethylenediamine are with ester group-aminated.Last and 2-acetyl mercapto succinyl oxide reacts, and generates title complex of the present invention and forms agent, and two isomer are always arranged in the reactions steps of back this moment.2. preparation is at its R
1In one-O-CO-CH is arranged
2-O-C
6H
4-CH
2-part of the present invention the time, be starting raw material with the tyrosine ester, at first prepare Z
1-protection compound, then with bromo-acetic acid tert-butyl with the phenolic hydroxyl group alkylation, fall amino protecting group by the method cracking of all knowing again.Tosylation and with quadrol with ester group-aminated (described in item 1), and then react with chloroacetyl chloride.By known method chlorine and thioacetic acid potassium or-sodium reaction and being substituted, the tert-butyl ester is acidic hydrolysis again.And can be randomly with the activated carboxylic of N-Hydroxysuccinimide, then with required biomolecular reaction with generation.3. work as R in the part of the present invention
1Be SCN-C
6H
4-CH
2When base, its method for making is, at first presses the phenylmethylamine sulfonylation of currently known methods with right-oil of mirbane alanine ester, and then with nitro hydrogenation, the fragrant amido of generation is protected, and for example reacts with chloroformic acid benzyl ester.Next as previously mentioned, be with quadrol with ester group-aminated, with the Thiovanic acid reaction of S-protection, carbobenzoxy-(Cbz) is fallen in cracking, introduces the isothiocyanic acid base with the thio phosgene reaction then.4. prepare X of the present invention
1During for the part of alkyl, at first the amino of glycinate is carried out tosylation,, make ester group-aminated then with reacting ethylenediamine with toluene sulfonyl chloride.The free amine group that generates is protected with butyloxycarbonyl (back claims the BOC yl), and the nitrogen N-alkylation by known method replaces tosyl group with idoalkane after the BOC base is fallen in cracking, with the reaction of 2-acetyl mercapto succinyl oxide, obtains isomer mixture this moment.5. R among preparation the present invention
1During for the part of amino butyl ester; at first the compound that the nitrogen-atoms of Methionin ester has been protected by BOC-with tosylation with another unprotected primary amino acidylate; carry out aminolysis with reacting ethylenediamine then; with the reaction of 2-acetyl mercapto succinyl oxide (have isomer mixture and produce this moment), fall amino protecting group with the currently known methods cracking more again.6. prepare R of the present invention
2During for the part of isothiocyanic acid phenyl, with glycine methyl ester and nitrobenzene sulfonyl chloride reaction, reduce nitro then, the amino that protection generates.Intermediate that obtains and reacting ethylenediamine carry out aminolysis, and the Thiovanic acid with the S-protection reacts again.Falling (BOC) protecting group by the currently known methods cracking. this free amine group reacts with thio phosgene again, generates corresponding isothiocyanic acid base.
Prepare the X of the metal complexes of general formula I of the present invention-wherein
1, X
2, X
3And/or R
3In at least two when being the metal ion Equivalent, in accordance with known methods title complex of the present invention is formed and add reductive agent in the agent (can obtain) by aforesaid method, be preferably tin (II) salt such as tin chloride or stannous tartrate, and randomly add the additive of the conventional usefulness of Galenicals, the buffer reagent compatible (as the Tris buffer reagent) as physiology, a spot of ionogen (as sodium-chlor), stablizer is (as gluconate, phosphoric acid salt, phosphonate) etc., sterilize as the aqueous solution, such solution can show the time spent for short metal isotropic substance of transformation period such as Tc-99m the aqueous solution of required metal ion is reacted, and also can obtain with metal-salt/oxide compound reaction in radiopharmaceuticals manufactory for the isotropic substance of long half time.For guaranteeing that the isotopic title complex of metal generates fully, generally excessive at least 100 times of the add-on of title complex formation agent, that is medicine of the present invention is except that containing required metal complexes, also has or not the title complex of metal to form agent, and be incorporated as suitable with its potassium salt form this moment.
The reaction soln that contains above-mentioned metal complexes needn't be reprocessed in principle, can directly use.
Because technetium can have multiple oxidation state to have (+7～-1), should add the stablizer that title complex forms agent, this can make active nucleus keep stable form, till reacting completely with title complex formation agent (part).This class stablizer is called transfer ligand or helps part, and is at first mutually compound with strictly determined oxidation state with metal, then with ligand exchange reaction in give purpose part (title complex formation agent) again.Help the example of part that glucoheptonic acid is arranged, tartrate, citric acid (salt that comprises them), or known other material of professional skill personnel.
The metal complexes that obtains can be randomly with pharmacology on acceptable radioactive carrier substance reaction, this class radioactivity carrier should have such character, that is: as radiopharmaceuticals the time, injectable is with, suction or oral application.Carrier substance for example has HSA, and aqueous buffer solution is as three (methylol) aminomethane (or its salt), phosphoric acid salt, and Citrate trianion, supercarbonate etc., sterilized water, physiological saline, isoosmotic muriate or bicarbonate solution, or normal blood plasma-ion are as Ca
2+, Na
+, K
+And Mg
2+
When the medical upper body planted agent of nuclear used medicine of the present invention, dosage was 10
-5-5 * 10
4Nmol/kg body weight, preferred dose are 10
-3～5 * 10
2Nmol/kg body weight (in metal complexes) is 70kg in the mean body weight, is each 1.85MBq～normally intravenous injection of 1.85GBq. usage as the required radioactivity dosage of diagnosis, arterial perfusion, abdominal injection, intratumor injection, its consumption are 0.1～1ml.Preferably use intravenous injection.
Have mentioned element metal ion metal complexes of the present invention and have tolerance and very high stability in the good body by the medicine that it is made.Title complex of the present invention forms the characteristics that agent also has easy mark, promptly at room temperature with condition of neutral pH under, it is very high that they and desired compound metal carry out the bonded yield.
The following examples are described further content of the present invention, but this does not limit the scope of the invention.Embodiment 1a) N-carbobenzoxy-(Cbz)-L-Tyrosine methyl ester
97.6g (0.5mol) L-Tyrosine methyl ester mixes in the 100ml dichloromethane solution with the 86g chloroformic acid benzyl ester under the room temperature mutually in the suspension of 500-1000ml methylene dichloride.Slowly splash into the 51g triethylamine then under cooling, stirring is spent the night.In 40 ℃ of rotary evaporation mixtures, residuum 750ml acetic acid ethyl dissolution, filtering insolubles.Filtrate is washed 3 times with saturated common salt solution, and drying concentrates recrystallization.Yield: 72%.Calculated value: C65.64% H5.82% N4.25% O24.29% measured value: benzyl N-carbobenzoxy-(Cbz)-2-[(4-hexyloxy C65.47% H5.98% N4.02%b))]-the 2-methyl aminoacetate
Under the room temperature 1.12g (10mmol) potassium tert.-butoxide being added to 3.29g (10mmol) embodiment 1a) made compound is in the solution of 50mlDMF.Add 2.12g (10mmol) iodohexane then in the solution of 10mlDMF, heat 110 ℃ 3 hours.Be cooled to room temperature, add ice, dichloromethane extraction, washed several times with water, drying is filtered, and concentrates.Through silica gel column chromatography, 19: 1 wash-outs of CH2Cl2/EE get light yellow oil 1.8g.Yield 44%.Calculated value: C69.71% H7.56% N3.39% O19.35% measured value: benzyl 2-[(4-hexyloxy C69.54% H7.69% N3.13%c))]-the 2-methyl aminoacetate
4.14g (10mmol) embodiment 1b) compound of the Z1 of preparation protection is in the solution of 50ml ethyl acetate, in the presence of 1.5g palladium carbon (10%), 50 ℃ of hydrogenations are reacted and are finished filtration catalizer, and steaming desolventizes, and gets the 2.7g colorless oil.Yield 97%.Calculated value: C68.79% H9.02% N5.01% O17.18% measured value: benzyl N-p-tosyl group-2-[(4-hexyloxy C68.64% H9.11% N5.09%d))]-the 2-methyl aminoacetate
8.38g (30mmol) embodiment 1c) Zhi Bei amine solvent is in the 30ml methylene dichloride, 0 ℃ adds 5.72g toluene sulfonyl chloride and 30ml dichloromethane solution down.Splash into the 3.0g triethylamine, stirring at room 1 hour under 0 ℃ of the vigorous stirring.After reacting completely, add frozen water, dichloromethane extraction merges organic phase for several times, with cold 10%HCl washing 2 times, 10%NaHCO3 washing 3 times, saturated common salt solution washing 2 times.Dry back concentrates silica gel column chromatography, methylene dichloride wash-out.Yield: 60%.Calculated value: C63.72% H7.21% N3.23% O18.45% S7.40% measured value: benzyl N-p-tosyl group-2-[(4-hexyloxy C63.48% H7.52% N3.02% S7.25%e))]-2-Padil [N-(2-amino-ethyl)] acid amides
433mg (1mmol) embodiment 1d) Zhi Bei tolylsulfonyl glycine ethyl ester under refluxad slowly is added drop-wise in the solution of 1.2g (20mmol) quadrol and 1ml anhydrous methylene chloride in 1ml anhydrous methylene chloride solution.Reaction is finished, vacuum concentration, residuum silica gel column chromatography, methanol-eluted fractions.Yield 42%.Calculated value: C62.45% H7.64% N9.10% O13.864% S6.95% measured value: benzyl N-p-tosyl group-2-[(4-hexyloxy C62.36% H7.81% N8.94% S6.80%f))]-2-Padil N-{2-N-[(3-carboxyl-2-mercapto ethanoyl-1-oxopropyl)]-the 2-amino-ethyl } acid amides
0.38g (2.2mmol) 2-acetyl mercapto succinyl oxide is added to embodiment 1e) preparation 1.00g (2.2mmol) amine in the solution of 10ml pyridine/DMF (50: 50), stirring at room 4 hours.Steaming desolventizes, and residuum is handled with 0.5NHCl, dichloromethane extraction.Get 420mg yellow oil, yield 31% behind the flash chromatography.Calculated value: C56.67% H6.50% N6.61% O20.13% S10.09% measured value: benzyl N-p-tosyl group-2-[(4-hexyloxy C56.41% H7.01% N6.43% S9.90%g))]-2-Padil-N-{2-N-[(3-carboxyl-2-mercapto ethanoyl-1-oxopropyl)]-the 2-amino-ethyl } the Tc-99m title complex of acid amides
1mg embodiment 1f) Zhi Bei compound dissolution adds 50 these solution of μ l in 0.1M phosphoric acid buffer pH8.5 in 100 μ l ethanol, mixes with 100 μ l 99m-Tc-glyconic acid solution then, places 15 minutes.The marking yield is measured with HPLC.Embodiment 2a) benzyl N-carbobenzoxy-(Cbz)-2-[(4-methoxyl group)]-the 2-methyl aminoacetate
Under the room temperature 1.12g (10mmol) potassium tert.-butoxide being added to 3.29g (10mmol) embodiment 1a) made alcohol is in the solution of 50mlDMF.Be added dropwise to 1.42g (10mmol) methyl iodide then in the solution of 10mlDMF, heat 110 ℃.Reaction is finished, and is cooled to room temperature, adds ice, dichloromethane extraction, and washed several times with water, drying is filtered, and concentrates.Through silica gel column chromatography, 19: 1 wash-outs of CH2Cl2/EE get 1.92g oily matter.Yield 56%.Calculated value: C66.46% H6.16% N4.08% O23.30% measured value: benzyl 2-[(4-methoxyl group C66.18% H6.41% N3.97% O23.30%b))]-the 2-methyl aminoacetate
3.43g (10mmol) embodiment 2a) compound of the Z1 of preparation protection is in the solution of 50ml ethyl acetate, in the presence of 1.5g palladium carbon (10%), room temperature hydrogenation is reacted and is finished, filtration catalizer, and steaming desolventizes.Yield 98%.Calculated value: C63.14% H7.23% N6.69% O22.94% measured value: benzyl N-p-tosyl group-2-[(4-methoxyl group C62.91% H7.36% N6.50%c))]-the 2-methyl aminoacetate
6.28g (30mmol) embodiment 2b) Zhi Bei amine solvent is in the 50ml methylene dichloride, 0 ℃ adds 5.72g toluene sulfonyl chloride and 30ml dichloromethane solution down.Splash into the 3.0g triethylamine, stirring at room 1 hour under 0 ℃ of the vigorous stirring.After reacting completely, add frozen water, dichloromethane extraction merges organic phase for several times, with cold 10%HCl washing 2 times, 10%NaHCO3 washing 3 times, saturated common salt solution washing 2 times.Dry back concentrates silica gel column chromatography, methylene dichloride wash-out.Yield: 76%.Calculated value: C59.46% H5.82% N3.85% O22.01% S8.82% measured value: benzyl N-p-tosyl group-2-[(4-methoxyl group C59.32% H6.03% N3.66% S8.64%d))]-2-Padil [N-(2-amino-ethyl)] acid amides
363mg (1mmol) embodiment 2c) Zhi Bei ester under refluxad slowly is added drop-wise to 600mg (10mmol) quadrol in the solution of 1ml anhydrous methylene chloride in 1ml anhydrous methylene chloride solution.Reaction is finished, vacuum concentration, and residuum adds ethanol system HCl, stirring at room 2 hours.Steaming desolventizes, the residuum recrystallization.Yield 49%.Calculated value: C58.29% H6.44% N10.73% O16.35% S8.19% measured value: benzyl N-p-tosyl group-2-[(4-methoxyl group C57.89% H6.84% N10.01% S7.52%e))]-2-Padil N-{2-N-[(3-carboxyl-2-mercapto ethanoyl-1-oxopropyl)]-the 2-amino-ethyl } acid amides
0.38g (2.2mmol) 2-acetyl mercapto succinyl oxide is added to embodiment 2d) preparation 941mg (2.2mmol) amine in the solution of 10ml pyridine/DMF (50: 50), stirring at room 4 hours.Steaming desolventizes, and residuum is handled with 0.5NHCl, dichloromethane extraction.Get 905mg yellow oil, yield 73% behind the flash chromatography.Calculated value: C53.08% H5.52% N7.43% O22.63% S11.34% measured value: benzyl N-p-tosyl group-2-[(4-methoxyl group C52.31% H5.45% N7.06% S11.61%f))]-2-Padil-N-{2-N-[(3-carboxyl-2-mercapto ethanoyl-1-oxopropyl)]-the 2-amino-ethyl } the Tc-99m title complex of acid amides
1mg embodiment 2e) Zhi Bei compound dissolution adds 50 these solution of μ l in 100 μ l ethanol, and with 250 μ l alcohol dilutions, pH8.5 mixes with the 0.1M phosphoric acid buffer, mixes with 100 μ l99m-Tc-glyconic acid solution then, places 15 minutes.Filter, the yield of mark is measured with HPLC.Embodiment 3a) benzyl N-carbobenzoxy-(Cbz)-2-[(4-dodecyloxy)]-the 2-methyl aminoacetate
Under the room temperature 1.12g (10mmol) potassium tert.-butoxide being added to 3.29g (10mmol) embodiment 1a) made alcohol is in the solution of 50mlDMF.Be added dropwise to 3.55g (12mmol) iodo dodecane then in the solution of 10mlDMF, heat 110 ℃ 3 hours.Reaction is finished, and is cooled to room temperature, adds ice, dichloromethane extraction, and washed several times with water, drying is filtered, and concentrates.Through silica gel column chromatography, CH2Cl2/EE 19:1 wash-out gets the 2.2g desired substance.Yield 44%.Calculated value: C72.40% H8.71% N2.81% O16.07% measured value: benzyl 2-[(4-dodecyloxy C72.08% H8.85% N2.68%b))]-the 2-methyl aminoacetate
4.98g (10mmol) embodiment 3a) compound of the Z1 of preparation protection is in the solution of 50ml ethyl acetate, in the presence of 1.5g palladium carbon (10%), 50 ℃ of hydrogenations are reacted and are finished (4 hours), filtration catalizer, and steaming desolventizes.Yield 91%.Calculated value: C72.69% H10.26% N3.85% O13.20% measured value: benzyl N-p-tosyl group-2-[(4-dodecyloxy C72.53% H 9.98% N3.82%c))]-the 2-methyl aminoacetate
10.91g (30mmol) embodiment 3b) Zhi Bei amine solvent is in the 50ml methylene dichloride, is added in 5.72g toluene sulfonyl chloride and the 30ml dichloromethane solution under 0 ℃.Splash into the 3.0g triethylamine, stirring at room 1 hour under 0 ℃ of the vigorous stirring.After reacting completely, add frozen water, dichloromethane extraction merges organic phase for several times, with cold 10%HCl washing 2 times, 10%NaHCO3 washing 3 times, saturated common salt solution washing 2 times.Dry back concentrates silica gel column chromatography, methylene dichloride wash-out.Yield: 75%.Calculated value: C67.28% H8.37% N2.71% O15.45% S6.19% measured value: benzyl N-p-tosyl group-2-[(4-dodecyloxy C66.96% H8.26% N2.60% S6.11%d))]-2-Padil [N-(2-amino-ethyl)] acid amides
3.3g (6.38mmol) embodiment 3c) Zhi Bei ester under refluxad slowly is added drop-wise to 1.92g (31.9mmol) quadrol in the solution of 20ml anhydrous methylene chloride in 20ml anhydrous methylene chloride solution.Reaction is finished, vacuum concentration, and the residuum recrystallization obtains the 2.3g white crystals.Yield 80%.Calculated value: C66.02% H8.68% N7.70% O11.73% S5.86% measured value: benzyl N-p-tosyl group-2-[(4-dodecyloxy C66.88% H8.80% N7.59% S5.76%e))]-2-Padil N-{2-N-[(3-carboxyl-2-mercapto ethanoyl-1-oxopropyl)]-the 2-amino-ethyl } acid amides
0.32g (1.8mmol) 2-acetyl mercapto succinyl oxide is added to embodiment 3d) preparation 1.00g (1.8mmol) amine in the solution of 10ml pyridine/DMF (50: 50), stirring at room 4 hours.Steaming desolventizes, and residuum is handled with 0.5NHCl, dichloromethane extraction.(silica gel EtOH/MeOH) gets 420mg yellow oil, yield 32% behind the flash chromatography.Calculated value: C60.06% H7.42% N5.84% O17.78% S8.91% measured value: benzyl N-p-tosyl group-2-[(4-dodecyloxy C59.76% H7.61% N5.77% S8.78%f))]-2-Padil-N-{2-N-[(3-carboxyl-2-mercapto ethanoyl-1-oxopropyl)]-the 2-amino-ethyl } the Tc-99m title complex of acid amides
1mg embodiment 3e) Zhi Bei compound dissolution is got 50 these solution of μ l in 100 μ l ethanol, mixes with 250 μ l 0.1M phosphoric acid buffer pH8.5, mixes with 100 μ l 99m-Tc-glyconic acid solution then, places 15 minutes, and the marking yield is measured with HPLC.Embodiment 4a) benzyl N-p-tosyl group-2-[(4-benzyloxy)]-2-Padil-N-{2-N-[(3-carboxyl-2-mercapto ethanoyl-1-oxopropyl)]-the 2-amino-ethyl } acid amides
Under the room temperature with 4.68g (10mmol) embodiment 16b) preparation amino-complex slowly be added drop-wise to 3.48g (20mmol) acetyl mercapto succinyl oxide in the solution of 50mlTHF in the solution of 150mlTHF, stirring is spent the night, then in-20 ℃ of crystallizations.Obtain the 2.8g white crystals.Yield: 44%.Calculated value: C58.02% H5.50% N6.55% O19.95% S9.99% measured value: benzyl N-p-tosyl group-2-[(4-benzyloxy C57.80% H5.72% N6.51% S9.85%b))]-2-Padil-N-{2-N-[(3-carboxyl-2-mercapto ethanoyl-1-oxopropyl)]-the 2-amino-ethyl } the Tc-99m title complex of acid amides
1mg embodiment 4a) Zhi Bei compound dissolution is got 50 these solution of μ l in 100 μ l ethanol, mixes with 250 μ l 0.1M phosphoric acid buffer pH8.5, mixes with 100 μ l 99m-Tc-glyconic acid solution then, places 15 minutes, and the marking yield is measured with HPLC.Embodiment 5a) N-p-tosyl group-(4-nitrophenyl)-alanine methyl ester
7.56g (30mmol) (4-nitro) phenylalanine methyl ester is suspended in the 30ml water, 0 ℃ is mixed in the 20ml diethyl ether solution with the 5.72g toluene sulfonyl chloride down.In 1 hour, add the anhydrous yellow soda ash of 3.0g, stirred overnight at room temperature under 0 ℃ of the vigorous stirring by part ground.Add entry, ethyl acetate extraction merges organic phase for several times, with 10% cold HCl washing 2 times, 10%NaHCO3 washing 3 times, saturated common salt solution washing 2 times.Dry back concentrates, and obtains the 8.6g yellow crystal.Yield: 76%.Calculated value: C53.96% H4.80% N7.40% O25.37% S8.47% measured value: N-p-tosyl group-(4-aminophenyl)-alanine methyl ester C53.79% H4.99% N7.29% S8.30%b)
2.0g (10mmol) methanol solution of N-p-tosyl group-(4-nitrophenyl)-alanine methyl ester is added to 500mg palladium carbon (10%) in the suspension of 25ml methyl alcohol, 55 ℃ of hydrogenations, and filtration catalizer, steaming desolventizes.Obtain the 1.4g white crystals, yield 76%.Calculated value: C58.60% H5.79% N8.04% O18.37% S9.20% measured value: N-p-tosyl group-{ 4-[N-(tertbutyloxycarbonyl)] aminophenyl }-alanine methyl ester C58.09% H5.99% N8.80% S9.01%c)
3.78g (10mmol) embodiment 5b) Zhi Bei amino-complex and 3g (30mmol) triethylamine mix (gas generation in the solution gradation of 50ml dioxane with 7.4 g (34mmol), two carbonic acid, two-tert-butyl ester! ).Stirring at room 3 hours in the impouring frozen water, is used ethyl acetate extraction 3 times.Merge organic phase, wash with water 3 times, saturated common salt water washing 1 time, dried over mgso concentrates recrystallization.Yield 89%.Calculated value: C58.91% H6.29% N6.25% O21.40% S7.15% measured value: N-p-tosyl group-{ 4-[N-(tertbutyloxycarbonyl)] aminophenyl }-L-Ala [N-(2-amino-ethyl)] acid amides C58.12% H6.69% N6.21% S6.59%d)
700mg (1.6mmol) N-p-tosyl group-{ 4-[N-(tertbutyloxycarbonyl)] aminophenyl }-alanine methyl ester slowly is added drop-wise to 450mg (7.5mmol) quadrol in the solution of 5ml anhydrous methylene chloride in 1ml anhydrous methylene chloride solution, reflux 8 hours.Reaction is finished, vacuum concentration, silica gel column chromatography, 9: 1 wash-outs of ethyl acetate/methanol.Yield 85%.Calculated value: C57.97% H6.77% N11.76% O16.79% S6.73% measured value: N-p-tosyl group-{ 4-[N-(tertbutyloxycarbonyl)] aminophenyl }-L-Ala [N-(chloro acetylamino ethyl)] acid amides C57.08% H6.12% N12.33% S6.41%e)
Under 0 ℃ 1.24g (11mmol) chloro-acetyl chloride is added to the amine of 4.77g (10mmol) embodiment 5d preparation in 10ml anhydrous methylene chloride solution in the drips of solution of 5ml anhydrous methylene chloride.(note: a large amount of heat releases), stirring is spent the night in the solution of 5ml anhydrous methylene chloride slowly to drip the 2.02g quadrol then.Reaction is finished, and adds entry, uses ethyl acetate extraction, is washed to neutrality, and drying concentrates, and gets the 2.77g white crystals.Yield 50%.Calculated value: C54.29% H6.01% N10.13% O17.38% S5.80% measured value: N-p-tosyl group-{ 4-[N-(tertbutyloxycarbonyl)] aminophenyl }-L-Ala [N-(2-acetyl mercapto) kharophen ethyl)] acid amides C53.76% H5.78% N9.66% S5.92%f)
Under the nitrogen atmosphere 238mg (2mmol) thioacetic acid potassium is added to the compound 553mg (1mmol) of embodiment 5e preparation and catalytic amount sodium iodide in the 5ml dry DMF in anhydrous DMF solution.110 ℃ were heated 3 hours.Be cooled to room temperature, be poured among the 1N hydrochloric acid 50ml, ethyl acetate extraction is washed to neutrality, and drying concentrates silica gel column chromatography, EtOAc/MeOH9: 1 wash-out.Yield 35%.Calculated value: C54.71% H6.12% N9.45% O18.90% S10.82% measured value: N-p-tosyl group-{ 4-aminophenyl }-L-Ala [N-(2-acetyl mercapto) kharophen ethyl)] amide hydrochloride C54.40% H6.45% N9.25% S10.04%g)
85mgN-p-tosyl group-{ 4-[N-(tertbutyloxycarbonyl)] aminophenyl }-L-Ala [N-(2-acetyl mercapto) kharophen ethyl)] acid amides is dissolved in the 2ml3M hydrochloric acid stirring at room 6 hours.Steaming desolventizes, and gets the 70mg white crystals.Yield 100%.Calculated value: C49.95% H5.53% N10.95% O15.12% S12.12% measured value: C49.32% H5.76% N10.20% S11.77%h) N-p-tosyl group-{ the different sulphur cyanogen of 4-aminophenyl }-L-Ala [N-(2-acetyl mercapto) kharophen ethyl) 1 amide hydrochloride
The 11.5mg thio phosgene kept away in the dichloromethane solution of a little be added drop-wise under the moisture in 53mg N-p-tosyl group-{ 4-aminophenyl }-L-Ala [N-(2-acetyl mercapto) kharophen ethyl)] amide hydrochloride and 20 μ l triethylamines and the 4ml dichloromethane solution.Stirring at room 4 hours.Steaming desolventizes, and gets the 45mg yellow crystal.Yield 84%.Calculated value: C51.67% H4.90% N10.48% O14.96% S17.99% measured value: N-p-tosyl group-{ 4-[N-(tertbutyloxycarbonyl)] aminophenyl }-L-Ala [N-(2-benzoyl sulfydryl) kharophen ethyl)] acid amides C50.99% H5.15% N10.21% S18.56% embodiment 6a)
2mmol (394mg) S-benzoyl-2-mercapto acetate and 4mmol (560 μ l) triethylamine and 2mmol (953mg) N-p-tosyl group-{ 4-[N-(tertbutyloxycarbonyl)] aminophenyl }-L-Ala [N-(2-amino-ethyl)] acid amides mixes under 10 ℃ of coolings mutually in the 5ml methylene dichloride.Add 2mmol (509mg) 1-benzotriazole oxygen base-three-(dimethylin) microcosmic salt-phosphofluoric acid muriate (back claims BOP-Cl) then, water cooling was stirred 4 hours down.Mix with water then, add 4N hydrochloric acid and make pH1-1.5.Dichloromethane extraction merges organic phase, NaHCO3 and water washing, and drying concentrates chromatography.Yield 60%.Calculated value: C58.70% H5.85% N8.56% O17.10% S9.79% measured value: N-p-tosyl group-{ 4-aminophenyl }-L-Ala [N-(2-benzoyl sulfydryl) kharophen ethyl)] acid amides C58.04% H6.03% N8.39% S9.30%b)
(10ml 30mmol) is added to the amine of 645mg (1mmol) embodiment 6a protection in the 5ml ethyl acetate solution to the 3M hydrochloric acid of prepared fresh in ethyl acetate.Stirring at room 30 minutes.Steaming desolventizes, and residuum is dry under vacuum.Yield 98%.Calculated value: C54.86% H5.29% N9.48% O13.53% S10.85% measured value: N-p-tosyl group-{ the different sulphur cyanogen of 4-aminophenyl }-L-Ala [N-(2-benzoyl sulfydryl) kharophen ethyl)] acid amides C53.90% H5.52% N9.09% S9.97%c)
The 115mg thio phosgene is kept away the title compound that is added drop-wise to 296mg (0.5mmol) embodiment 6b under the moisture and 200 μ l triethylamines in the 4ml dichloromethane solution in the dichloromethane solution of a little.Stirring at room 4 hours.Steaming desolventizes, and residuum is dissolved in chloroform, with the washing of 0.1% citric acid, NaHCO
3Solution washing 2 times, water washing 1 time.Drying concentrates, and gets the 45mg yellow crystal.Yield 85%.Calculated value: C56.35% H4.73% N9.39% O13.14% S16.12% measured value: N-(3-oil of mirbane alkylsulfonyl)-glycine methyl ester C56.31% H4.98% N9.08% S17.01% embodiment 7a)
25.11g (0.2mol) glycine methyl ester is dissolved in the 500ml methylene dichloride, 0 ℃ drips 44.32g 3-nitrobenzene sulfonyl chloride down in the 100ml dichloromethane solution.In 1 hour, splash into the 3.0g triethylamine in the 50ml dichloromethane solution under 0 ℃ of the vigorous stirring., stirring at room 1 hour.(thin layer tracking) adding frozen water after reacting completely, dichloromethane extraction merges organic phase for several times, and with 10% cold HCl washing 2 times, 10%NaHCO3 washs 3 times, saturated common salt solution washing 2 times.Dry back concentrates yield: 82%.Calculated value: N-(3-amino phenyl sulfonyl acyl group)-glycine methyl ester C39.42% H3.68% N10.22% O35.00% S11.69% measured value C40.31% H3.37% N9.89% S11.04%b)
2.74g (10mmol)-nitro-compound of embodiment 7a in the solution of 50ml acetate in the presence of 1.5g palladium carbon (10%), room temperature hydrogenation, filtration catalizer, steaming desolventizes, yield 90%.Calculated value: C44.26% H4.95% N11.47% O26.20% S13.13% measured value: N-(3-amino phenyl sulfonyl acyl group)-glycine-[N '-(2-amino-ethyl)] acid amides C4401% H5.11% N12.08% S12.76%c)
1g (3.6mmol) N-(3-amino phenyl sulfonyl acyl group)-glycine methyl ester is added in 2.5ml anhydrous methylene chloride drips of solution and slowly is added drop-wise to 2.2g (36mmol) quadrol under the reflux in the solution of 2.5ml anhydrous methylene chloride.Reaction is finished, vacuum concentration, silica gel column chromatography, 9: 1 wash-outs of methylene chloride.Yield 76%.Calculated value: C44.11% H5.92% N20.57% O17.63% S11.78% measured value: N-[(3-amino phenyl sulfonyl acyl group C43.09% H6.41% N21.82% S10.68%d))]-glycine-[N '-[(acetyl mercapto) ethanoyl (2-amino-ethyl)] } acid amides
250mg (1.08mmol) SATA (SIGMA company, 1994, A9043) in the solution of THF at 0 ℃, argon atmospher with keep away in the solution of the amine that slowly is added drop-wise to 272mg (1mmol) embodiment 7c preparation under the moisture and anhydrous THF.Stirred stirring at room 12 hours 2 hours in 0 ℃.Steaming desolventizes, residuum silica gel column chromatography, 9: 1 wash-outs of methylene chloride.Yield 60%.Calculated value: C43.29% H5.19% N14.42% O20.59% S16.51% measured value: N-[(3-isothiocyano benzenesulfonyl C42.45% H5.23% N15.64% S15.36%e))]-glycine-[N '-[(acetyl mercapto) ethanoyl (2-amino-ethyl)] } acid amides
The 65mg thio phosgene kept away in the dichloromethane solution of a little is added drop-wise to 200mg N-[(3-amino phenyl sulfonyl acyl group under the moisture)]-glycine-{ [N '-[(acetyl mercapto) ethanoyl (2-amino-ethyl)] } acid amides and 20 μ l triethylamines are in the 4ml dichloromethane solution.Stirring at room 4 hours.Steaming desolventizes, and residuum is dissolved in chloroform, with the washing of 0.1% citric acid, NaHCO3 solution washing 2 times, water washing 1 time.Drying concentrates, and gets the 197mg yellow crystal.Yield 89%.Calculated value: C41.85% H4.21% N13.01% O18.58% S22.35% measured value: N-carbobenzoxy-(Cbz)-uncle O--Ding oxygen carbonyl methyl (L-Tyrosine methyl ester) C40.44% H3.93% N12.57% S23.66% embodiment 8a)
3.29g embodiment 1a) L-Tyrosine methyl ester of made Z1-protection is dissolved in the dry DMF, adds 1.12g (10mmol) potassium tert.-butoxide.After 30 minutes, be added dropwise to the 1.95g bromo-acetic acid tert-butyl, heat 110 ℃ 4 hours, stirring at room is 4 hours then.Add entry, dichloromethane extraction, washing, drying is filtered, and concentrates.Through silica gel column chromatography, 19: 1 wash-outs of CH2C12/EE get 2.5g oily matter.Yield 57%.Calculated value: C65.00% H6.59% N3.16% O25.25% measured value: O-(uncle-Ding oxygen carbonyl methyl) L-Tyrosine methyl ester C64.65% H6.82% N3.09%b)
1.5g (3.4mmol) embodiment 8a) compound of the Z1 of preparation protection is in the solution of 50ml ethyl acetate, in the presence of 1.5g palladium carbon (10%), 50 ℃ of hydrogenations are reacted and are finished, filtration catalizer, and steaming desolventizes, and obtains the 1.0g colorless oil.Yield 99%.Calculated value: C62.12% H7.49% N4.53% O25.86% measured value: N-p-tosyl group-uncle O--Ding oxygen carbonyl methyltyrosine methyl esters C61.88% H7.67% N4.47%c)
920mg O-(uncle-Ding oxygen carbonyl methyl) L-Tyrosine methyl ester is dissolved in the methylene dichloride, and 0 ℃ of following Dropwise 5 70mg toluene sulfonyl chloride is in the solution of methylene dichloride.Slowly splash into the 300mg triethylamine, stirring is spent the night.Add frozen water, dichloromethane extraction merges organic phase, with cold 10%HCl washing 2 times, 10%NaHCO3 washing 2 times, saturated common salt solution washing 2 times.The drying back concentrates, and adds ether and handles, and gets the 900mg white crystals.Yield: 65%.Calculated value: C59.60% H6.31% N3.02% O24.16% S6.92% measured value: N-p-tosyl group-uncle O--Ding oxygen carbonyl methyl-[N-(2-amino-ethyl)] tyrosine acid amides C59.38% H6.55% N3.08% S6.66%d)
3.0g (6.5mmol) dichloromethane solution of N-p-tosyl group-uncle O--Ding oxygen carbonyl methyltyrosine methyl esters is added drop-wise in the solution of methylene dichloride of 5g quadrol.Reflux 4 hours after the cooling, adds entry, and separately two-phase with dichloromethane extraction for several times, merges organic phase, washing, and drying concentrates.Silica gel column chromatography, methanol-eluted fractions gets the 1.5g colorless oil.Yield 47%.Calculated value: C58.64% H6.77% N8.55% O19.53% S6.52% measured value: N-p-tosyl group-O-carboxymethyl-[N-(2-amino-ethyl)] tyrosine acid amides C58.39% H6.91% N8.38% S6.56%e)
The 2ml trifluoroacetic acid is added to embodiment 8d under the room temperature) preparation 491mg (2.2mmol) tert-butyl ester in the solution of 25ml methylene dichloride, stirring at room.Reaction is finished, and vacuum is steamed and removed trifluoroacetic acid, and residuum dissolves with methylene dichloride, water washing, and drying concentrates yield 83%.Calculated value: C55.16% H5.79% N9.65% O22.04% S7.36% measured value: N-p-tosyl group-O-carboxymethyl-tyrosine [N-(2-(piperonyl sulfydryl) kharophen ethyl)] acid amides C53.88% H5.64% N10.02% S7.44%f)
The THF solution of 350mg (1.08mmol) piperonyl Thiovanic acid-N-hydroxy-succinamide ester in 0 ℃, argon atmospher and keep away in 2 hours, be added drop-wise to 435mg (1mmol) embodiment 8e under the moisture) amine of preparation is in anhydrous THF solution.Stirring at room 12 hours.Steaming desolventizes, residuum silica gel column chromatography, CH2Cl2/MeOH/HOAc9: 1: 0.1 wash-out.Yield 58%.Calculated value: C55.98% H5.17% N6.53% O22.37% S9.96% measured value: N-p-tosyl group-O-carboxymethyl-tyrosine { N-[2-(mercaptoethyl) amino-ethyl] } acid amides C55.38% H5.04% N6.68% S9.09%g)
The compound of the S-protection that under the room temperature 644mg (1mmol) embodiment 8f is prepared and the phenylmethylether of tracer level are added in the 10ml trifluoroacetic acid.Ebuillition of heated reacts and finishes for a moment, and vacuum is steamed and removed trifluoroacetic acid, and residuum is dissolved in the The suitable solvent and washes, and drying is concentrated, chromatography.Yield 34%.Calculated value: C51.85% H5.34% N8.25% O21.98% S12.59% measured value: the Tc-99m title complex of N-tosyl group-O carboxymethyl-tyrosine { N-[2-(mercaptoethyl) amino-ethyl] } acid amides C51.62% H5.53% N8.68% S13.61%h)
1mg embodiment 8g) Zhi Bei compound dissolution is in 100 μ l ethanol, get 50 these solution of μ l and be added in the 250 μ l 0.1M phosphoric acid buffer pH8.5, and add 50 μ l citric acid solutions (the 50mg trisodium citrate is dissolved in 1ml water) and 2.5 μ l stannous chloride solutions (5.0mgSn (II) Cl2 is dissolved in 0.1NHCl).Add 100 μ l 99m-Tc-then and produce liquid, placed 15 minutes.Measure the mark yield with HPLC.Embodiment 9a) cholesterol Diethylene Glycol (DEG-cholesterol)
54.1g (100mmol) cholesterol tosylate and 106g Diethylene Glycol are in solution reflux (thin layer tracking) under nitrogen atmosphere of the anhydrous dioxane of 250ml.After reacting completely, add entry, dichloromethane extraction, silica gel column chromatography, CH2Cl2/MeOH9: 1 wash-out gets colorless solid.Yield 81%.Calculated value: C78.43% H11.46% O10.11% measured value: cholesterol-2-chloroethyl (ethylene glycol) C76.99% H12.32%b)
Under nitrogen atmosphere, 4.75d (10mmol) the DEG-cholesterol of embodiment 9a preparation is mixed with the Powdered triphenyl phosphine of 3.14g (12mmol) in the 50ml anhydrous carbon tetrachloride solution.Reflux.The cooling back adds 50ml sherwood oil or hexane, in-20 ℃ of cooling for some time. and filter collection precipitation, the method that goes up is for another example handled, up to precipitation no longer occurring.Drying concentrates.Silica gel column chromatography, CH2Cl2/MeOH9: 1 wash-out, get 3.70g, be oily matter.Yield 75%.Calculated value: C75.49% H10.83% O6.49% measured value: N-carbobenzoxy-(Cbz)-2-[(4-cholesterol-two (ethylene glycol) benzyl C74.73% H11.74%c)]-the 2-methyl aminoacetate
The cholesterol cpds 493mg (1mmol) of embodiment 9b preparation is added to the N-carbobenzoxy-(Cbz) L-Tyrosine methyl ester of embodiment 1a preparation and 183mg (1mmol) salt of wormwood in 10ml toluene in the solution of 10ml toluene.Reflux 6 hours.After reacting completely, be cooled to room temperature, concentrate silica gel column chromatography, 1: 1 wash-out of petrol ether/ethyl acetate.Yield: 29%.Calculated value: C73.46% H9.78% N1.86% O14.89% measured value: 2-[(4-cholesterol-two (ethylene glycol) benzyl C73.28% H10.01% N1.70%d)]-2-methyl aminoacetate hydrochloride
The compound 7.52g (10mmol) of the Z protection of embodiment 9c preparation is dissolved in 50ml3MHCl in ethyl acetate, stirring at room 6 hours.Steaming desolventizes, and gets the 6.02g white crystals.Yield: 93%.Calculated value: C71.53% H9.66% N2.04% O11.62% measured value: N-carbobenzoxy-(Cbz)-2-[(4-cholesterol-two (ethylene glycol) benzyl C71.82% H9.39% N2.01%e)]-the 2-methyl aminoacetate
The amine 19.53g (30mmol) of embodiment 9d preparation is dissolved in the 50ml methylene dichloride, and 0 ℃ is mixed in the 30ml dichloromethane solution with the 5.72g toluene sulfonyl chloride down.Splash into the 3.0g triethylamine, stirring at room 1 hour under 0 ℃ of the vigorous stirring.After reacting completely, add frozen water, dichloromethane extraction merges organic phase for several times, with cold 10%HCl washing 2 times, 10%NaHCO3 washing 3 times, saturated common salt solution washing 2 times.Dry back concentrates silica gel column chromatography, methylene dichloride wash-out.Yield: 77%.Calculated value: C71.52% H8.88% N1.74% O13.86% S3.98% measured value: N-p-tosyl group-2-[(4-cholesterol-two (ethylene glycol) benzyl C70.89% H9.02% N1.66% S3.70%f)]-2-Padil [N-(2-amino-ethyl)] acid amides
The dichloromethane solution of the tosyl group glycinate of 806mg (1mmol) embodiment 9e preparation is added drop-wise to 1.2g quadrol (20mmol) in the solution of 1ml methylene dichloride.Reflux, reaction is finished, vacuum concentration.The residuum silica gel column chromatography, methanol-eluted fractions.Yield 85%.Calculated value: C70.55% H9.06% N5.04% O11.51% S3.84% measured value: N-p-tosyl group-2-[(4-cholesterol-two (ethylene glycol) benzyl C69.24% H9.31% N4.83% S3.71%g)]-2-Padil-N-{2-N-[(3-carboxyl-2-sulfydryl ethanoyl-1-oxopropyl)] amino-ethyl acid amides
0.38g under the room temperature (2.2mmol) 2-ethanoyl mercaptosuccinic acid acid anhydride is added to embodiment 9f) preparation amine 1,83g (2.2mmol) in 10ml pyridine/DMF (50: 50) solution, stirring at room 4 hours.Reaction is finished, and steaming desolventizes, residuum 0.5N salt acid treatment, and the methylene dichloride dissolving, flash chromatography gets the 887mg yellow oil.Yield 40%.Calculated value: C65.51% H8.10% N4.17% O15.87% S6.36% measured value: N-p-tosyl group-2-[(4-cholesterol-two (ethylene glycol) benzyl C63.66% H7.58% N3.99% S7.41%h)]-2-Padil-N-{2-N-[(3-carboxyl-2-sulfydryl ethanoyl-1-oxopropyl)] amino-ethyl the Tc-99m title complex of acid amides
The part of 1mg embodiment 9g preparation is dissolved in the 100 μ l ethanol, get 50 these solution of μ l and be added in the 250 μ l 0.1M phosphoric acid buffer pH8.5, and add 50 μ l citric acid solutions (the 50mg trisodium citrate is dissolved in 1ml water) and 2.5 μ l stannous chloride solutions (5.0 mgSn (II) Cl2 is dissolved in 0.1NHCl).Add 50 μ l 99m-Tc-then and produce liquid, placed 15 minutes.Measure the mark yield with HPLC.Embodiment 10a) 1-tosyl group-1,4,7-three azepines heptan-3-ketone
25.73g (0.1mol) the tosyl group glycine methyl ester refluxes in anhydrous methylene chloride solution and is added drop-wise to 30g (0.5mol) quadrol in the solution of 50ml anhydrous methylene chloride down.Stirring at room 12 hours.Reaction is finished, and vacuum concentration obtains the 24g yellow oil.Yield 88%.Calculated value: C48.69% H6.32% N15.49% O17.69% S11.82% measured value: 7-N-tertbutyloxycarbonyl 1-tosyl group-1 C47.23% H6.67% N15.34% S11.54%b); 4,7-three azepines heptan-3-ketone
27g (100mmol) embodiment 10a) Zhi Bei amino-complex mixes in 500ml dioxane and the gradation of 74g (340mmol) two carbonic acid two-tert-butyl ester.Stirring at room 3 hours in the impouring frozen water, is used ethyl acetate extraction 3 times.Merge organic phase, wash with water 3 times, saturated common salt water washing 1 time, dried over mgso concentrates, and recrystallization gets the 27.9g white crystals.Yield 75%.Calculated value: C51.74% H6.78% N11.31% O21.54% S8.63% measured value: 7-N-tertbutyloxycarbonyl 1-n-hexyl-1-tosyl group-1 C51.41% H6.96% N11.12% S8.91%c); 4, under 7-three azepines heptan-3-ketone room temperature 5g salt of wormwood being added to 3.71g (10mmol) embodiment 10b) sulphonamide of preparation is in 50mlDMF.Then 2.54g (12mmol) iodohexane is splashed into the solution of 10mlDMF, heat 110 ℃ 3 hours.Reaction is finished, and is cooled to room temperature, in the impouring frozen water, uses dichloromethane extraction.Merge organic phase, wash with water for several times, drying concentrates the residuum re-crystallizing in ethyl acetate.Yield 89% calculated value: C58.00% H8.19% N9.22% O17.56% S7.04% measured value: 1-n-hexyl-1-tosyl group-1,4 C57.37% H7.87% N9.01% S6.95%d), 7-three azepines heptan-3-ketone
0 ℃ of following embodiment 10c) Zhi Bei 456mg (1mmol) sulphonamide is added in the 10ml trifluoroacetic acid stirring at room 2 hours.Reaction is finished, in the impouring ice.Add NaHCO3 and make weak baseization, extraction concentrates drying.Yield 94%.Calculated value: C57.44% H8.22% N11.82% O13.50% S9.02% measured value: 10-ethanoyl-9-carboxymethyl-1-n-hexyl-1-tosyl group-10-sulfo--1 C57.96% H8.01% N11.63% S8.75%e); 4,7-three azepines heptan-3-ketone
Under the room temperature 3.55g (10mmol) amino-complex slowly is added drop-wise to 1.91g (20mmol) acetyl mercapto succinyl oxide in 20mlDMF solution in the solution of 10mlDMF.Stirring is spent the night.Then in the hydrochloric acid of impouring half volumetric molar concentration.Dichloromethane extraction, silica gel column chromatography, EtOH/MeOH wash-out are earlier to be 1: 1 after 9: 1.Yield 66%.Calculated value: C52.16% H6.66% N7.93% O21.15% S12.11% measured value: 10-ethanoyl-9-carboxymethyl-1-n-hexyl-1-tosyl group-10-sulfo--1 C52.85% H6.87% N7.52% S11.66%f); 4, the Tc-99m title complex of 7-three azepines heptan-3-ketone
1mg N; N[hexyl-p-tosyl group] glycyl-N-[(3-carboxyl-2-mercapto ethanoyl-1-oxopropyl)] amino-ethyl acid amides is dissolved in the 100 μ l ethanol; get 50 these solution of μ l with 100 μ l alcohol dilutions; add in the 100 μ l 0.1M phosphoric acid buffer pH7.5, and add 100 μ l 99m-Tc-glyconic acid solution.Mark yield＞95% (silica gel, 95% ethanol).Embodiment 11a) N-α-tosyl group-N-ε-tertbutyloxycarbonyl lysine methyl ester 2.6g (10mmol) N-ε-tertbutyloxycarbonyl lysine methyl ester is dissolved in the 50ml anhydrous pyridine, and 0 ℃ adds the 1.91mg toluene sulfonyl chloride down.Placed 24 hours down for 4 ℃.In the impouring ice, filter collection precipitation, recrystallization.Yield: 78%.Calculated value: C55.05% H7.30% N6.76% O23.16% S7.74% measured value: N-α-tosyl group-N-ε-tertbutyloxycarbonyl Methionin [N-(2-amino-ethyl)] acid amides C54.67% H7.42% N6.64% S7.54%b)
The tosyl group Methionin ester of 415mg (1mmol) embodiment 11a preparation slowly is added drop-wise to 600mg quadrol (10mmol) in the solution of 1ml anhydrous methylene chloride in 1ml anhydrous methylene chloride solution.Reflux, reaction is finished, vacuum concentration.The residuum recrystallization.Yield 59%.Calculated value: C54.28% H7.74% N12.66% O18.08% S7.25% measured value: N-α-tosyl group C54.54% H7.57% N12.18% S7.06%c)--N-ε-tertbutyloxycarbonyl Methionin [N-(2-(piperonyl sulfydryl) kharophen ethyl)] acid amides
With the THF solution of 350mg (1.08mmol) piperonyl Thiovanic acid-N-hydroxy-succinamide ester in 0 ℃, argon atmospher and keep away be added drop-wise to 443mg (1mmol) embodiment 11b under the moisture) amine of preparation is in anhydrous THF solution.Placed 2 hours down for 0 ℃.Stirring at room 12 hours.Steaming desolventizes, residuum silica gel column chromatography, CH2Cl2/MeOH/9: 1: wash-out.Yield 54%.Calculated value: C55.37% H6.51% N8.61% O19.67% S9.85% measured value: N-α-tosyl group one Methionin [N-(2-(piperonyl sulfydryl) kharophen ethyl)] acid amides C55.22% H6.85% N8.41% S9.66%d)
651mg N-α-tosyl group-N-ε-tertbutyloxycarbonyl Methionin [N-(2-amino-ethyl)] acid amides is dissolved in 5ml 3MHCl in the solution of ethyl acetate.Stirring at room 6 hours, steaming desolventizes, and gets the 530mg white crystals.Yield: 96%.Calculated value: C54.63% H6.05% N10.19% O17.46% S11.67% measured value: N-α-tosyl group C54.40% H6.47% N10.01% S11.84% embodiment 12a)--N-ε-tertbutyloxycarbonyl-Methionin [N-(2-(benzoyl sulfydryl) kharophen ethyl) 1 acid amides
With the THF solution of 316mg (1.08mmol) benzoyl Thiovanic acid-N-hydroxy-succinamide ester in 0 ℃, argon atmospher and keep away be added drop-wise to 443mg embodiment 11b under the moisture) amine of preparation is in anhydrous THF solution.Placed stirring at room 12 hours 2 hours for 0 ℃.Steaming desolventizes, residuum silica gel column chromatography, CH2Cl2/MeOH/9: 1: wash-out.Yield 65%.Calculated value: C56.11% H6.50% N9.03% O18.04% S10.33% measured value: N-α-tosyl group-Methionin [N-(2-(benzoyl sulfydryl) kharophen ethyl)] acid amides C56.98% H6.86% N8.88% S10.05%b)
The title compound of 621mg embodiment 12a is dissolved in 5ml 3MHCl in the solution of ethyl acetate.Stirring at room 6 hours, steaming desolventizes, and gets the 500mg white crystals.Yield: 90%.Calculated value: C51.74% H5.97% N10.06% O14.36% S11.51% measured value: the Tc-99m title complex of N-α-tosyl group-Methionin [N-(2-(benzoyl sulfydryl) kharophen ethyl)] acid amides C51.40% H6.14% N10.10% S11.48%c)
The amine of 10mg embodiment 12b preparation is molten to be mixed with 500 μ l 1NNaOH, places 15 minutes.Get 50 these solution of μ l, adding 250 μ l 0.1M phosphoric acid buffers, to make pH be in 8.5 and 50 μ l citric acid solutions (the 50mg trisodium citrate is dissolved in 1.0ml water) and the 2.5 μ l tin protochlorides (5.0mgSn (II) Cl2 and 1.0ml 0.1NHCl), add 50 μ l 99m-Tc-then and produce liquid, placed 15 minutes.Measure mark yield (＞95%) embodiment 13a with HPLC) N-[3-(N-tertbutyloxycarbonyl) amino phenyl sulfonyl acyl group]-glycine methyl ester
2.12g (10mmol) embodiment 7b) Zhi Bei amino-complex and 3g triethylamine (30mmol) mix (gas generation) in the 50ml dioxane with the gradation of 7.4g (34mmol) two carbonic acid two-tert-butyl ester.Stirring at room 3 minutes in the impouring frozen water, is used ethyl acetate extraction 3 times.Merge organic phase, water and saturated common salt water washing 3 times, dried over mgso concentrates recrystallization.Yield 85%.Calculated value: C48.83% H5.85% N8.13% O27.88% S9.31% measured value: N-[3-(N-tertbutyloxycarbonyl) amino phenyl sulfonyl acyl group C47.44% H5.93% N8.57% S9.66%b)]-glycine [N '-(2-amino-ethyl)] acid amides
12.11g (35mmol) glycinate of embodiment 13a preparation slowly is added drop-wise to 42g quadrol (700mmol) in the solution of 100ml dry toluene in the solution of 250ml toluene/dioxane (can choose wantonly and only use toluene).Reflux, reaction is finished, vacuum concentration.Residuum is dissolved in chloroform, washing.Yield 78%.Calculated value: C44.06% H6.16% N13.70% O19.56% S7.84% measured value: N-[3-(N-tertbutyloxycarbonyl) amino phenyl sulfonyl acyl group C45.44% H6.63% N14.57% S7.66%c)]-glycine N '-[(S-benzoyl sulfydryl) ethanoyl]-(2-amino-ethyl)] acid amides
5mmol (0.98g) S-benzoyl-2-mercapto acetate mixes under 10 ℃ of coolings with the 50ml methylene dichloride mutually with the amine of 10mmol (1.4ml) triethylamine and 5mmol (1.86g) embodiment 13b preparation.Add 5.5mmol (1.375g) BOP-Cl then, (becoming clarification after 10-20 minute), restir 1 hour are stirred in water cooling down.Mix with water then, add 4N hydrochloric acid and make pH1-1.5.Dichloromethane extraction merges organic phase, NaHCO3 and water washing, and drying concentrates chromatography.Yield 62%.Calculated value: C52.16% H5.84% N10.14% O20.27% S11.60% measured value: C53.44% H6.63% N10.57% S11.66%d) N-[3-(N-amino phenyl sulfonyl acyl group]-glycine N '-[(S-benzoyl sulfydryl) ethanoyl]-(2-amino-ethyl)] acid amides
(10ml, solution 30mmol) are added to the amine of protection of 552mg (1mmol) embodiment 13c preparation in the 5ml ethyl acetate solution to the 5ml 3M hydrochloric acid of prepared fresh in ethyl acetate.Stirring at room 30 minutes.Steaming desolventizes, and residuum is drying at room temperature under vacuum.Yield 93%.Calculated value: C46.86% H4.76% N11.51% O16.43% S13.1 7% measured value: N-[3-isothiocyano amino phenyl sulfonyl acyl group C45.44% H5.33% N10.57% S13.66%e)]-glycine N '-[(S-benzoyl sulfydryl) ethanoyl]-(2-amino-ethyl)] acid amides
With the 65mg thio phosgene in the dichloromethane solution of a little keep away the N-[3-that is added drop-wise to 200mg embodiment 13d preparation under the moisture (N-amino phenyl sulfonyl acyl group]-glycine N '-[(S-benzoyl sulfydryl) ethanoyl]-(2-amino-ethyl)] acid amides and 20 μ l triethylamines are in the 4ml dichloromethane solution.Stirring at room 4 hours.Steaming desolventizes, and residuum is dissolved in chloroform, and with the washing of 0.1% citric acid, sodium chloride solution washing 2 times, water washing 1 time, drying concentrates chromatography.Yield 66%.Calculated value: C48.77% H4.09% N11.37% O16.24% S19.53% measured value: N-benzenesulfonyl-O-methoxy carbonyl methyl [N-(2-amino-ethyl)] tyrosine acid amides C48.44% H4.63% N11.75% S20.06% embodiment 14a)
Embodiment 8e) feed HCl gas in Zhi Bei amine 4.35g (10mmol) and the 100ml anhydrous methanol to saturated, stirring is spent the night.Steaming desolventizes, and obtains crystallization.Yield 92%.Calculated value: C51.90% H5.81% N8.65% O19.75% S6.60% measured value: N-benzenesulfonyl-O-methoxy carbonyl methyltyrosine [N-(2-trityl sulfydryl) acetylamino ethyl)] acid amides C51.59% H5.93% N8.47% S6.49%b)
The THF solution of 4.66g (10.8mmol) S trityl Thiovanic acid-N-hydroxy-succinamide ester is added drop-wise to 4.35g (10mmol) embodiment 14a under 0 ℃, argon atmospher) amine of preparation and 2.02g triethylamine be in the THF/ aqueous solution.Placed stirring at room 12 hours 2 hours down for 0 ℃.Steaming desolventizes, residuum silica gel column chromatography, CH2Cl2: wash-out.Yield 68%.Calculated value: C65.86% H5.66% N5.49% O14.62% S8.37% measured value: N-benzenesulfonyl-O-methoxy carbonyl methyltyrosine [N-(2-trityl sulfydryl) acetylamino ethyl)] acid amides C65.66% H5.71% N5.36% S8.21%c)
The methyl esters 766mg (1mmol) of embodiment 14b preparation is added to methyl alcohol system KOH solution, stirring at room in the solution of 2.5ml methyl alcohol.Reaction is finished, and steaming desolventizes, and the sylvite water treatment is adjusted to chloroform extraction after the weakly alkaline.Organic phase washes with water, and drying concentrates.Yield: 63%.Calculated value: C65.49% H5.50% N5.59% O14.90% S8.53% measured value: C65.26% H5.72% N5.43% S8.43%d) the N-benzenesulfonyl-[(HOOC-Trp-Ile-Asp-Leu-His-Gly-NH)-carbonyl methyltyrosine [N-(2-trityl sulfydryl) acetylamino ethyl)] acid amides
In 0 ℃ and 5 minutes, 206mg (1mmol) dicyclohexylcarbodiimide is added to embodiment 14c in the drips of solution of 2mlDMF) preparation sour 1mmol (980mg) and 115mg (1mmol) N-hydroxy-succinamide in the solution of 2ml dry DMF, stirred 30 minutes in 0 ℃, under 0 ℃ and argon atmospher, add 1mmol (853mg) peptide H2N-Gly-His-Leu-Asp-Ile-Trp (according to Barany and Merryfield in 30 minutes then, The Peptides:Analysis, Biology, Academic Press, New York, 1980; Steward and Young, Solid Phase Peptides Syntheses, the 2nd edition, Pierce Chemical W., Rockford, II, 1984) and 304mg (3mmol) triethylamine in the solution of 10ml dry DMF.Stirring at room 12 hours.Add 200 μ l acetate, restir 30 minutes, the filtering dicyclohexylurea (DCU), residuum concentrates, and stirs with ether, obtains white solid, DMF/ ether recrystallization.Yield 35%.Calculated value: C62.07% H6.29% N4.04% O16.13% S4.04% measured value: C61.77% H6.52% N4.32% S4.34%e) the N-benzenesulfonyl-[(HOOC-Trp-Ile-Asp-Leu-His-Gly-NH)-carbonyl methyltyrosine [N-(sulfydryl) acetylamino ethyl)] acid amides
The compound-s of the protection that under the room temperature 530mg (0.3mmol) embodiment 14d is prepared and the phenylmethylether of tracer level are added in the 10ml trifluoroacetic acid.Ebuillition of heated a moment, then, vacuum is steamed and is removed trifluoroacetic acid, and residuum is dissolved among the THF, concentrates chromatography.Yield 59%.Calculated value: C56.67% H6.32% N13.42% O18.87% S4.73% measured value: C56.14% H6.48% N12.98% S4.81%f) the N-benzenesulfonyl-[(HOOC-Trp-Ile-Asp-Leu-His-Gly-NH)-the Tc-99m title complex of carbonyl methyltyrosine [N-(sulfydryl) acetylamino ethyl)] acid amides
1mg embodiment 14e) Zhi Bei compound dissolution is got 50 these solution of μ l and is added in the 100 μ l 0.1M phosphoric acid buffer pH9.5 in 100 μ l ethanol/waters 1: 1, adds 100 μ l 99m-Tc-glucose acid solutions, measures the mark yield with HPLC.(LiChrospher?RP18，H2O/MeCN+0.1％TFA)。Embodiment 15a) N-benzenesulfonyl-O-tert-butoxycarbonylmethyl tyrosine [N-(2-benzoyl sulfydryl) acetylamino ethyl)] acid amides
The compound of 2mmol (394mg) S-benzoyl-2-mercapto acetate and 4mmol (560 μ l) triethylamine and 2mmol (982mg) embodiment 8d preparation mixes mutually with the 5ml methylene dichloride and is cooled to 10 ℃.Add 2mmol (509mg) BOP-Cl then, water cooling was stirred 12 hours down.Mix with water then, add 4N hydrochloric acid and make pH1-1.5.Dichloromethane extraction merges organic phase, NaHCO3 and water washing, and drying concentrates chromatography.Yield 76%.Calculated value: C59.18% H5.86% N6.27% O19.11% S9.58% measured value: N-benzenesulfonyl-O-carboxymethyl tyrosine [N-(2-benzoyl sulfydryl) acetylamino ethyl)] acid amides C60.88% H5.89% N5.63% S8.74%b)
Embodiment 15c under the room temperature) compound-s of the 644mg (1mmol) of preparation protection adds stirring at room in the 10ml trifluoroacetic acid.Reaction is finished, and vacuum is steamed and desolventized.Residuum is dissolved in ethyl acetate, and water washing concentrates drying, chromatography.Yield 77%.Calculated value: C56.76% H5.09% N6.85% O20.86% S10.45% measured value: N-benzenesulfonyl-[(HOOC-Trp-Ile-Ile-Asp-Leu-(D-Trp)-NH)-carbonyl methyltyrosine [N-(2-benzoyl sulfydryl) acetylamino ethyl)] acid amides C57.14% H5.68% N7.23% S11.31%c)
In 0 ℃ and 5 minutes, 206mg (1mmol) dicyclohexylcarbodiimide is added to embodiment 15b in the drips of solution of 2mlDMF) preparation sour 1mmol (614mg) and 115mg (1mmol) N-hydroxy-succinamide in the solution of 2ml dry DMF, stirred 30 minutes in 0 ℃, under 0 ℃ and argon atmospher, add 1mmol (845mg) peptide H2N-(D-Tyr)-Leu-Asp-Ile-Ile-Trp (according to Barany and Merryfield in 30 minutes then, peptide class: analyze, biological, (the ThePeptides:Analysis of Science Press, Biology, Academic Press), New York, 1980; Stewardand Young, solid phase peptide synthesizes (Solid Phase Peptides Syntheses), the 2nd edition, PierceChemical W., Rockford, II, 1984) and 304mg (3mmol) triethylamine in the anhydrous solution of 10ml dry DMF.Stirring at room 12 hours.Add 200 μ l acetate, restir 30 minutes, the filtering dicyclohexylurea (DCU), residuum concentrates, with ebullient tetrahydrofuran (THF) extraction 2 times.Merging filtrate, drying concentrates, and silica gel column chromatography methylene dichloride wash-out obtains white solid.Yield 40%.Calculated value: C60.86% H6.23% N10.69% O17.77% S4.45% measured value: the Tc-99m title complex of N-benzenesulfonyl-[(HOOC-Trp-Ile-Ile-Asp-Leu-(D-Trp)-NH)-carbonyl methyltyrosine [N-(2-benzoyl sulfydryl) acetylamino ethyl)] acid amides C60.77% H6.42% N10.32% S4.65%d)
2mg embodiment 15c) Zhi Bei compound dissolution is in 100 μ l ethanol, mix with 100 μ l 1NNaOH, after 15 minutes, get 50 these solution of μ l be added in the 250 μ l 0.1M phosphoric acid buffer pH8.5 and 50 μ l citric acid solution (the 50mg trisodium citrate is dissolved in 1.0ml) water and 2.5 μ l stannous chloride solutions (5.0mg Sn (II) Cl2 and 1.0ml 0.1NHCl) in, add 50 μ l 99m-Tc-then and produce liquid, placed 15 minutes.Measure mark yield (＞95%) with HPLC.Embodiment 16a) N-tosyl group-L-Tyrosine methyl ester-4-benzyl oxide
Under 0 ℃ 32.58g (171mmol) Tosyl chloride is added to 50g (155.37mmol) L-Tyrosine methyl ester-4-benzyl oxide hydrochloride in the solution of 300ml pyridine in the drips of solution of 100ml pyridine.0 ℃ was stirred 3 hours.Evaporated in vacuo, residuum are dissolved in the dissolving of 500ml methylene dichloride.This organic phase and the jolting of 300ml 5N hydrochloric acid 2 times, organic phase be through dried over mgso, evaporated in vacuo.Residuum small amount of methanol recrystallization.Obtain 68.29g colourless crystallization powder.Yield 93%.Calculated value: C65.58% H5.73% N3.19% S7.29% measured value: 2-(4-benzyloxy benzyl)-1-tosyl group-1,4 C65.30% H5.81% N3.02% S7.18%b), 7-three azepines heptan-3-ketone
45g (102.38mmol) embodiment 16a) title substance was added to 1 liter of 1 in 1 hour, stirred 3 hours in 80 ℃ then.Solvent evaporated.Residuum and 200ml water stir.Filter collection precipitation washes with water, and 60 ℃ of vacuum-dryings obtain the cream-colored amorphous powder of 46.91g.Yield 98%.Calculated value: C64.22% H6.25% N8.95% S6.86% measured value: 9-chloro-2-(4-benzyloxy benzyl)-1-tosyl group-1,4 C64.05% H6.17% N9.05% S6.78%c), the 7-three azepine ninth of the ten Heavenly Stems-3,8-diketone
10g (21.39mmol) embodiment 16b) title compound is dissolved in the 100ml chloroform, adds 2.38g (23.53mmol) triethylamine.Drip 2.66g (23.53mmol) chloro-acetyl chloride in the solution of 20ml chloroform in 0 ℃ in following 30 minutes.Stirred 30 minutes in 0 ℃.Add 200ml 1N hydrochloric acid, vigorous stirring.Tell organic phase, dried over mgso, evaporated in vacuo, residuum small amount of methanol recrystallization obtains cream-colored crystalline solid.Yield 89%.Calculated value: C59.61% H5.56% N7.72% S5.89% Cl6.52% measured value: 10-benzoyl-2-(4-benzyloxy benzyl)-1-tosyl group-10-sulfo--1 C59.50% H5.69% N7.55% S5.71% Cl6.38%d); 4; the 7-three azepine ninth of the ten Heavenly Stems-3, the 8-diketone
The title compound of 9g (16.54mmol) embodiment 16c is dissolved in the 100ml chloroform, adds 1.67g (16.54mmol) triethylamine.Add 2.29g (16.54mmol) thiobenzoic acid then, reflux 10 minutes.Be cooled to room temperature, with 2N hydrochloric acid jolting 1 time, 5% sodium carbonate solution jolting 1 time, organic phase is through dried over mgso, vacuum-evaporation.Residuum small amount of methanol recrystallization obtains 9.61g colourless crystallization powder yield 90%.Calculated value: C63.24% H5.46% N6.51% S9.93% measured value: 10-benzoyl-2-(4-benzyloxy benzyl)-1-tosyl group-10-sulfo--1 C63.15% H5.57% N6.40% S9.81% embodiment 17a); 4; the 7-three azepine last of the ten Heavenly stems-3, the 8-diketone
The title compound of 9g (16.54mmol) embodiment 16c is dissolved in the 100ml chloroform, adds 1.67g (16.54mmol) triethylamine.Add 1.28g (16.54mmol) thioacetic acid then, reflux 10 minutes.Be cooled to room temperature, with 2N hydrochloric acid jolting 1 time, 5% sodium carbonate solution jolting 1 time, organic phase is through dried over mgso, vacuum-evaporation.Residuum small amount of methanol recrystallization obtains the 8.20g colourless crystallization.Yield 85%.Calculated value: C59.67% H5.70% N7.20% S10.98% measured value: 10-trifluoroacetyl group-2-(4-benzyloxy benzyl)-1-tosyl group-10-sulfo--1 C59.51% H5.81% N7.05% S10.80% embodiment 18a); 4; the 7-three azepine last of the ten Heavenly stems-3, the 8-diketone
9g (16.54mmol) embodiment 16c) title compound is dissolved in the 100ml chloroform, adds 1.67g (16.54mmol) trifluoromethyl thioacetic acid, reflux 10 minutes.Be cooled to room temperature, with 2N hydrochloric acid jolting 1 time, 1% sodium carbonate solution jolting 1 time, organic phase is through dried over mgso, vacuum-evaporation.Residuum acetone recrystallization obtains the 8.75g colourless crystallization. yield 83%.Calculated value: C54.62% H4.74% N6.59% S10.05% F8.94% measured value: N-methane sulfonyl-L-Tyrosine methyl ester-4-benzyl oxide C54.47% H4.61% N6.50% S9.90% F8.81% embodiment 19a)
Under 0 ℃ 19.58g (171mmol) methane sulfonyl chloride is added to 50g (155.37mmol) L-Tyrosine methyl ester-4-benzyl oxide hydrochloride in the solution of 300ml pyridine.0 ℃ was stirred 3 hours.Evaporated in vacuo, residuum are dissolved in the dissolving of 500ml methylene dichloride.This organic phase and the jolting of 300ml 5N hydrochloric acid 2 times, organic phase be through dried over mgso, evaporated in vacuo.Residuum small amount of methanol recrystallization.Obtain 53.64g colourless crystallization powder.Yield 95%.Calculated value: C59.49% H5.82% N3.85% S8.82% measured value: 2-(4-benzyloxy benzyl)-1-methane sulfonyl-1,4 C59.30% H5.95% N3.71% S8.70%b), 7-three azepines heptan-3-ketone
37.2g title compound (102.38mmol) embodiment 19a) was added to 1 liter of 1 in 1 hour, stirred 3 hours in 80 ℃ then.Solvent evaporated.Residuum and 200ml water stir.Filter collection precipitation is washed with massive laundering, and 60 ℃ of vacuum-dryings are spent the night, and obtains the cream-colored amorphous powder of 37.68g.Yield 97%.Calculated value: C56.97% H6.64% N11.07% S8.45% measured value: 9-chloro-2-(4-benzyloxy benzyl)-1-methane sulfonyl-1,4 C56.81% H6.72% N10.93% S8.32%c), the 7-three azepine ninth of the ten Heavenly Stems-3,8-diketone
10g (26.35mmol) embodiment 19b) title compound is dissolved in the 100ml chloroform, adds 2.93g (28.99mmol) triethylamine.Drip 3.27g (28.99mmol) chloro-acetyl chloride in the solution of 20ml chloroform in 0 ℃ in following 30 minutes.Stirred 30 minutes in 0 ℃.Add 200ml 1N hydrochloric acid, vigorous stirring.Tell organic phase, dried over mgso, evaporated in vacuo, residuum small amount of methanol recrystallization obtains cream-colored crystalline solid 10.93g.Yield 91%.Calculated value: C52.68% H5.75% N9.22% S7.03% Cl7.78% measured value: 10-benzoyl-2-(4-benzyloxy benzyl)-1-methane sulfonyl-10-sulfo--1 C52.51% H5.85% N9.13% S6.90% Cl7.68%d); 4; the 7-three azepine ninth of the ten Heavenly Stems-3, the 8-diketone
7.54g (16.54mmol) title compound of embodiment 19c is dissolved in the 100ml chloroform, adds 1.67g (16.54mmol) triethylamine.Add 2.29g (16.54mmol) thiobenzoic acid then, reflux 10 minutes.Be cooled to room temperature, with 2N hydrochloric acid jolting 1 time, 5% sodium carbonate solution jolting 1 time, organic phase is through dried over mgso, vacuum-evaporation.Residuum small amount of methanol recrystallization obtains 8.11g colourless crystallization powder yield 88%.Calculated value: C58.15% H5.60% N7.53% S11.50% measured value: 9-chloro-2-(4-acrinyl)-1-tosyl group-1,4 C58.03% H5.71% N7.61% S11.38% embodiment 20a), the 7-three azepine ninth of the ten Heavenly Stems-3,8-diketone
The title compound of 20g (36.76mmol) embodiment 16c is dissolved in the 200ml methylene dichloride, adds 2ml acetate.Add 3g palladium-carbon catalyst (10%) then, hydrogenation is spent the night, and catalyzer filters, and evaporated in vacuo obtains the 16.52g amorphous solid.Yield: 99%.Calculated value: C52.92% H5.33% N9.26% S7.06% Cl7.81% measured value: 9-chloro-2-(4-palm acyl-oxygen benzyl)-1-tosyl group-1 C52.81% H5.26% N9.11% S6.93% Cl7.72%b); 4; the 7-three azepine ninth of the ten Heavenly Stems-3, the 8-diketone
10g (22.03 mmol) embodiment 20a) Zhi Bei title compound is dissolved in the 100ml chloroform, adds 2.45g triethylamine (23.53mmol).Drip 6.66g (24.23mmol) palmityl chloride in following 10 minutes in 0 ℃, under this temperature, stirred 2 hours.With the jolting of 200ml 2N acetate, dried over mgso organic phase, evaporate to dryness, residuum silica gel column chromatography, 20: 1 wash-outs of methylene dichloride/acetone obtain the 11.90g waxy solid.Yield 78%.Calculated value: C62.45% H7.86% N6.07% S4.63% Cl5.12% measured value: 10-benzoyl-2-(4-palm acyl-oxygen benzyl)-1-tosyl group-10-sulfo--1 C62.28% H7.70% N5.89% S4.54% Cl4.98%c); 4; the 7-three azepine ninth of the ten Heavenly Stems-3, the 8-diketone
8g (11.55mmol) embodiment 20b) Zhi Bei title compound is dissolved in the 100ml chloroform, adds 1.17g triethylamine (11.55 mmol).Add 1.60g (11.55mmol) thiobenzoic acid, reflux 10 minutes.Be cooled to room temperature, respectively wash 1 time with 2N hydrochloric acid and 5% sodium carbonate solution.The dried over mgso organic phase, evaporate to dryness, the residuum silica gel column chromatography, 20: 10: 1 wash-outs of dichloromethane/hexane/acetone obtain the colourless chip solid of 8.53g (from ether).Yield 93%.Calculated value: C65.04% H7.49% N5; 29% S8.07% measured value: C64.90% H7.55% N5; 15% S7.91% embodiment 21a) 3-cholesterol monomethyl succinate and 9-chloro-2-(4-acrinyl)-1-tosyl group-1; 4; the 7-three azepine ninth of the ten Heavenly Stems-3; title compound and 10.72g (22.03mmol) the cholesterol monomethyl succinate of phenyl ester 10g (22.03mmol) the embodiment 20a that the 8-diketone forms are dissolved among the 49mlDMF; be cooled to 0 ℃, add 300mg 4-dimethylamino pyridine and 5.45g (26.44mmol) dicyclohexylcarbodiimide then.0 ℃ was stirred 3 hours, and stirred overnight at room temperature adds the 50ml ether, the filtering urea, and filtrate is with the dilution of 250ml ethyl acetate, with 200ml water jolting 5 times.Organic phase is through dried over mgso, evaporated in vacuo, and residuum is through silica gel column chromatography, and 10: 5: 1 wash-outs of dichloromethane/hexane/ethyl acetate obtain the 17.60g waxy solid.Yield 78%.Calculated value: C66.39% H7.87% N4.55% S3.48% Cl3.84% measured value: 10-benzoyl-2-(4-acrinyl)-1-tosyl group-10-sulfo--1 C66.28% H7.95% N4.47% S3.31% Cl3.70%b); 4; the 7-three azepine last of the ten Heavenly stems-3, the phenyl ester of 8-diketone and cholesterol succinic acid half-ester
The title compound of 6g (6.50mmol) embodiment 21a is dissolved in the 50ml chloroform, adds 0.66g (6.50mmol) triethylamine.Add 0.9g (6.50mmol) thiobenzoic acid then, reflux 10 minutes.Be cooled to room temperature, with 2N hydrochloric acid jolting 1 time, 5% sodium carbonate solution jolting 1 time, organic phase is through dried over mgso, vacuum-evaporation.Residuum small amount of methanol recrystallization obtains 6.06g wax print crystalline substance.Yield 91%.Calculated value: C68.01% H7.58% N4.10% S6.26% measured value: 7-N-(tertbutyloxycarbonyl)-2-(4-benzyloxy benzyl)-1-tosyl group-1 C67.85% H7.43% N3.98% S6.17% embodiment 22a); 4,7-three azepines heptan-3-ketone
20g (42.77mmol) embodiment 106b) title compound is dissolved in the 200ml chloroform, adds 4.76g (47.05mmol) triethylamine.Add 10.27g (47.05mmol) two carbonic acid two-tert-butyl ester in the solution of 50 chloroforms in 0 ℃ of following gradation.Stirring at room 5 hours, with 5% sodium carbonate solution washing 3 times, dried over mgso, vacuum-evaporation, residuum small amount of methanol recrystallization gets the 22.34g colourless crystallization.Yield 92%.Calculated value: C63.47% H6.57% N7.40% S5.65% measured value: 7-N-tertbutyloxycarbonyl-2-(4-acrinyl)-1-tosyl group-1 C63.31% H6.42% N7.45% S5.49%b); 4; 7-three azepines heptan-3-ketone 21g, (title compound of 36.99mmol (embodiment 22a) was dissolved in the 300ml methylene dichloride, adds 4g palladium-carbon catalyst (10%).Hydrogenation is spent the night.Filtration catalizer, the filtrate evaporate to dryness.Get 16.39g glass foam shape thing, moments later hardening, yield 99%.Calculated value: C57.84% H6.54% N8.80% S6.71% measured value: 7-N-tertbutyloxycarbonyl-2-(4-(benzyloxy carbo methoxy group)-benzyl)-1-tosyl group-1 C57.70% H6.61% N8.69% S6.54%c); 4,7-three azepines heptan-3-ketone
15g (33.51mmol) embodiment 22b) title compound, 7.68g (33.51mmol) benzyl acetate bromide and 13.8g (100mmol) salt of wormwood were in 300ml acetonitrile reflux 24 hours.Filtering salt, the filtrate evaporate to dryness concentrates, and residuum is dissolved in the 200ml methylene dichloride, 100ml washing 2 times, the organic phase dried over mgso, residuum silica gel column chromatography dichloromethane/hexane/acetone 20/10/1 wash-out gets the 10.69g colorless oil.Yield: 51% calculated value: C61.42% H6.28% N6.72% S5.12% measured value: 1-tosyl group-2-(4-(benzyloxy carbo methoxy group)-1-4 C61.27% H6.09% N6.68% S5.13%d); 7 ,-three azepines-heptan-3-ketone (being trifluoroacetate)
10g (15.98mmol) embodiment 22c) stirred 1 hour under title compound and the 100ml trifluoroacetic acid room temperature.Evaporated in vacuo concentrates, and gets the glassy foam of 10.22g, places sclerosis.Yield 100%.Calculated value: C54.45% H5.04% H6.57% S5.01% F8.91% measured value: 9-chloro-2-(4-(benzyloxy carbo methoxy group)-benzyl)-1-tosyl group-1 C54.51% H5.10% H6.43% S4.89% F9.15%e); 4; the 7-three azepine ninth of the ten Heavenly Stems-3, the 8-diketone
10g (15.62mmol) embodiment 22d) title compound and 4.75g (46.90mmol) triethylamine are dissolved in the 200ml chloroform.0 ℃ splashes into 1.94g (17.19mmol) chloro-acetyl chloride in following 30 minutes, stirs 2 hours in 0 ℃ then.Organic phase is with 5% hydrochloric acid and each jolting of water 2 times; dried over mgso; vacuum is steamed and to be desolventized, and residuum is through silica gel column chromatography, 20: 1 wash-outs of dichloromethane/ethyl acetate; get 7; the cured shape solid of 62g, yield 81% calculated value C57.85% H5.36% N6.98% S5.32% Cl5.89% measured value C57.70% H5.49% N6.82% S5.25% Cl5.78%f) 9-chloro-2 (4-(carboxymethoxyl)-benzyl)-1-tosyl group-1,4; the 7-three azepine ninth of the ten Heavenly Stems-3, the 8-diketone
7g (11.63mmol) embodiment 22e) title compound is dissolved in the 150ml methylene dichloride; add 2gq palladium carbon (10%) catalyzer; hydrogenation is spent the night; filtration catalizer; the filtrate evaporated in vacuo; get 5.89g vitreous solid yield 99% calculated value: C51.61% H5.12% N8.21% S6.26% Cl6.92% measured value: 10-ethanoyl-2-(4-(carboxymethoxyl)-benzyl)-1-tosyl group-10-sulfo--1 C51.45% H5.03% N8.13% S6.11% Cl6.79%g); 4; the 7-three azepine last of the ten Heavenly stems-3, the 8-diketone
5g (9.77mmol) embodiment 22f) title compound is dissolved in the 80ml chloroform, adds 1.98g (19.53mmol) triethylamine.The interior 0.74g (9.77mmol) of adding thioacetic acid also refluxes to add and flowed 10 minutes.5% hydrochloric acid that solution impouring 200ml is ice-cold, vigorous stirring is told organic phase, dried over mgso, evaporated in vacuo, silica gel column chromatography, 3: 1 wash-outs of hexane/ethyl acetate get this title compound of 4.47g, are vitreous solid.Yield: 83% calculated value: C52.26% H5.30% N7.62% S11.62% measured value: 10-ethanoyl-2-(4-(carboxymethoxyl)-benzyl)-1-tosyl group-10-sulfo--1 C52.11% H5.39% N7.50% S11.49%h); 4; the 7-three azepine last of the ten Heavenly stems-3, the N-hydroxy-succinamide ester of 8-diketone
4g (7.25mmol) embodiment 22g) title compound, 1.65g (7.98mmol) dicyclohexylcarbodiimide, 30mg 4-dimethylamino pyridine and 0.92g (7.98mmol) N-hydroxy-succinamide are dissolved in the 20ml chloroform in 0 ℃, 0 ℃ was stirred 1 hour, room temperature restir 24 hours, add ether 20ml, the dicyclohexylurea (DCU) that filtering is separated out, filtrate vacuum-evaporation.The residuum silica gel column chromatography; methylene dichloride/dioxane wash-out; get the 4.09g colorless solid; yield 87% calculated value: C51.84% H4.97% N8.64% S9.88% measured value: 10-ethanoyl-2-(4-carboxymethoxyl)-benzyl C51.58% H4.80% N8.53% S9.68% embodiment 23a))-1-methylsulfonyl-10-sulfo--1; 4; the 7-three azepine last of the ten Heavenly stems-3, the 4-nitro phenyl ester of 8-diketone
4g (7.25mmol) embodiment 22g) be dissolved in the 20ml chloroform under 0 ℃ of title compound, 1.11g (7.97mmol) 4-nitrophenol, 30mg 4-dimethylamino pyridine and 1.65g (7.97mmol) dicyclohexylcarbodiimide, 0 ℃ was stirred 3 hours down.Stirring at room 24 hours; add ether 20ml; the precipitation that filtering is separated out; the filtrate vacuum concentration; the residuum silica gel column chromatography; methylene dichloride/dioxane wash-out (15: 1); get 3.85g cheese look solid; yield 79% calculated value: C53.56% H4.79% N8.33% S9.53% measured value: 10-ethanoyl-2-(4-(carboxymethoxyl)-benzyl)-1-tosyl group-10-sulfo--1 C53.41% H4.63% N8.17% S9.38% embodiment 24a); 4; the 7-three azepine last of the ten Heavenly stems-3, the 8-diketone
4 (7.25mmol) embodiment 22g) is dissolved in the 20ml chloroform under 0 ℃ of title compound 1.47g (7.97mmol) pentafluranol, 30mg 4-dimethylamino pyridine and 1.65g (7.97mmol) dicyclohexylcarbodiimide.0 ℃ was stirred 3 hours down, and room temperature restir 24 hours adds the 20ml ether, the precipitation that filtering is separated out, filtrate vacuum concentration.The residuum silica gel column chromatography, methylene dichloride/dioxane wash-out gets the 3.95g colorless solid.Yield 76% calculated value: C50.20% H3.93% N5.85% S8.93% F13.24 measured value: 7-N-tertbutyloxycarbonyl-2-(4-benzyloxy benzyl)-1-methane sulfonyl-1 C50.05% H3.87% N5.69% S8.71% F13.03% embodiment 25a); 4,7-three azepines heptan-3-ketone
16.23g title compound (42.77mmol) embodiment 19b) is dissolved in the 200ml chloroform, adds 4.76g (47.05mmol) triethylamine.Splash into 10.27g (47.05mmol) tert-Butyl dicarbonate under 0 ℃ in the 50ml chloroformic solution, 0 ℃ was stirred 30 minutes.Stirring at room is 5 hours then.With 5% sodium carbonate solution washing 3 times.The organic phase dried over mgso.Vacuum is steamed and is desolventized, and residuum small amount of methanol recrystallization gets 20.19g spumescence solid.Yield 96%.Calculated value: C58.64% H6.77% N8.55% S6.52% measured value: 7-N-tertbutyloxycarbonyl-2-(promise of 4-hydroxyl benzyl)-1-methane sulfonyl-1,4 C58.48% H6.59% N8.41% S6.42%b), 7-three azepines heptan-3-ketone
20g (40.68mmol) embodiment 25a) title compound is dissolved in the 300ml methylene dichloride, adds 4g palladium carbon (10%) catalyzer, and hydrogenation is spent the night.Filtration catalizer, the filtering evaporate to dryness gets the glassy foam of 16.17g, the tablet after fixing.Yield 99%.Calculated value: C50.86% H6.78% N10.47% S7.99% measured value: 7-N-tertbutyloxycarbonyl-2-(4-benzyloxy carbo methoxy group)-benzyl C50.70% H6.69% N10.31% S7.78%c))-1-methane sulfonyl-1; 4,7-three azepines heptan-3-ketone
15g (37.36mmol) embodiment 25b) title compound, 8.56g (37.36mmol) benzyl acetate bromide and 13.8g (100mmol) salt of wormwood reflux 24 hours in the 300ml acetonitrile.Filtering salt, filtrate evaporate to dryness, residuum are dissolved in the 200ml methylene dichloride, with 100ml washing 2 times, organic phase dried over mgso, vacuum-evaporation.Residuum is through silica gel column chromatography; ethyl acetate/hexane/acetone/20/10/1 wash-out; get 10.06g spumescence solid; yield 49% calculated value: C56.82% H6.42% N7.64% S5.83% measured value: 2-(4-(benzyloxy carbo methoxy group)-benzyl)-1-methane sulfonyl-1 C56.65% H6.35% N7.51% S5.72%d); 4,7-three azepines heptan-3-ketone (being trifluoroacetate)
10g (18.19mmol) embodiment 25c) title compound stirring at room 1 hour in the 100ml trifluoroacetic acid.Evaporated in vacuo gets the glassy foam of 9.95g, places hardening.Yield: 97% calculated value: C49.02% H5.01% N7.46% S5.69% F10.11% measured value: 9-chloro-2-(4-(benzyloxy carbo methoxy group)-1-methane sulfonyl-1 C48.91% H4.90% N7.30% S5.51% F 9.96%e); 4; the 7-three azepines-ninth of the ten Heavenly Stems-3, the 8-diketone
9g (15.97mmol) embodiment 25d) title compound, 1.78g (17.57mmol) triethylamine are dissolved in the 200ml chloroform.0 ℃ drips 1.98g (17.57mmol) chloro-acetyl chloride in following 30 minutes.0 ℃ was stirred 2 hours, and organic phase is respectively washed 2 times with 5% hydrochloric acid and water.Dried over mgso, evaporated in vacuo.Residuum is through silica gel column chromatography; 20: 1 wash-outs of dichloromethane/ethyl acetate; yield: 83% calculated value: C52.52% H5.37% N7.99% S6.09% Cl6.74% measured value: 9-chloro-2-(4-(carboxymethoxyl)-benzyl)-1-methane sulfonyl-1 C52.37% H5.43% N7.81% S5.93% Cl6.58%f); 4; the 7-three azepine ninth of the ten Heavenly Stems-3, the 8-diketone
6.5g title compound (12.36mmol) embodiment 25e) is dissolved in the 150ml methylene dichloride, adds 2g palladium carbon (10%) catalyzer, hydrogenation is spent the night.Filtration catalizer, the filtrate evaporated in vacuo gets 5.33% vitreous solid, yield: 99%.Calculated value: C44.09% H5.09% N9.64% S7.36% Cl8.13% measured value: 10-ethanoyl-2-(4-(carboxymethoxyl)-benzyl)-1-methane sulfonyl-10-sulfo--1 C43.93% H4.95% N9.52% S7.22% Cl8.03%g); 4; the 7=three azepine last of the ten Heavenly stems-3, the 8-diketone
5g (11.47mmol) embodiment 22f) title compound is dissolved in the 80ml chloroform, adds 1.98g (19.53mmol) triethylamine.Add 0.74g (9.77mmol) thioacetic acid, heating down 10 minutes refluxes.Solution is poured into 5% freezing hydrochloric acid, and vigorous stirring is separated organic phase, dried over mgso, evaporated in vacuo.The silica gel column chromatography purifying, 3: 1 wash-outs of hexane/ethyl acetate.Get the 4.64g vitreous solid.Yield 85%.Calculated value: C45.46% H5.30% N8.84% S13.48% measured value: 10-ethanoyl-2-(4-(carboxymethoxyl)-benzyl)-1-methane sulfonyl-10-sulfo--1 C45.28% H5.17% N8.61% S13.38%h); 4; the 7-three azepine last of the ten Heavenly stems-3, the N-hydroxy-succinamide ester of 8-diketone
4g (8.41mmol) embodiment 25f) title compound, 1.91g (9.25mmol) dicyclohexylcarbodiimide, 30mg 4-dimethylamino pyridine and 1.06g (9.25mmol) N-hydroxy-succinamide are dissolved in the 20ml chloroform under 0 ℃, stirred 1 hour under this temperature.Again in stirring at room 24 hours.Add ether 20ml, the dicyclohexylurea (DCU) that filtering settles out.The filtrate evaporated in vacuo.Residuum is through silica gel column chromatography, and 10: 1 wash-outs of methylene dichloride/dioxan get the cream-colored solid of 3.47g.Yield: 72%.Calculated value: C46.15% H4.93% N9.78% S11.20% measured value: 10-ethanoyl-2-(4-(carboxymethoxyl)-benzyl)-1-methane sulfonyl-10-sulfo--1 C46.03% H4.83% N9.64% S11.05% embodiment 26a); 4; the 7-three azepine last of the ten Heavenly stems-3; 8-diketone and glycerine-1, the 3-glyceryl ester of 2-dipalmitate.
2g (5.27mmol) embodiment 25g) title compound, 20mg 4-dimethylamino pyridine, 3.30g (5.80mmol) glycerine-1,2-dipalmitate and 1.20g (5.80mmol) dicyclohexylcarbodiimide is dissolved in the 5ml chloroform under 0 ℃, under this temperature, stirred 3 hours, stirring at room 24 hours, add the 20ml ether, the filtering precipitation.Filter vacuum-evaporation, residuum are through silica gel column chromatography, and hexane, 30: 1 wash-outs of ethyl acetate get the cured shape solid of 3.35g.Yield 62%.Calculated value: C62.02% H8.94% N4.09% S6.25% measured value: N-methane sulfonyl tyrosine-4-benzyl oxide C61.91% H8.75% N3.91% S6.18% embodiment 27a)
10g (27.5mmol) embodiment 19a) title compound and 5.50g (137.6mmol) sodium hydroxide reflux 3 hours in 50ml water/50ml alcohol mixture.Be evaporated to dried.Residuum and 200ml 3N hydrochloric acid stirring at room 2 hours.The acid that the filter collection is separated out.Washing, 70 ℃ of vacuum-dryings.Get the cream-colored solid of 9.42g.Yield: 98%.Calculated value: C58.44% H5.48% N4.01% S9.18% measured value: 6,6 '-two-(1-N-tertbutyloxycarbonyl-1,4-diaza-own-3-ketone)-disulphide C58.28% H5.37% N3.91% S9.02%b)
10g (65.67mmol) cystamine, 11.50g (65.67mmol) N-Boc-glycine and 14.90g (72.24mmol) dicyclohexylcarbodiimide are dissolved in the 50ml tetrahydrofuran (THF) under 0 ℃, stirred 2 hours under this temperature.Stirring at room 12 hours.Add the 50ml ether, the precipitation that filtering is separated out, residuum is through silica gel column chromatography, and 6: 1 wash-outs of hexane/acetone get the 20.84g vitreous solid, yield: 68%.Calculated value: C46.33% H7.34% N12.01% S13.74% measured value: 6,6 '-two-(1,4-diaza-own-3-ketone)-disulphide C46.15% H7.28% N11.93% S13.67%c)
20g (42.86mmol) embodiment 27b) title compound is dissolved in the 100ml trifluoroacetic acid, stirring at room 2 hours.Be evaporated to dried.Residuum dissolves with 300ml 10% sodium carbonate solution, 50ml chloroform extraction 6 times.The combined chloroform phase; dried over mgso; evaporated in vacuo; get the 10.96g yellow solid; yield 96%. calculated values: C36.07% H6.81% N21/03% S24.07% measured value: 9,9 '-two-(2-(4-benzyloxy benzyl)-1-methane sulfonyl-1,4 C35.91% H6.90% N20.89% S23.89%d); the 7-three azepine ninth of the ten Heavenly Stems-3, the 6-diketone)-disulphide
9g (25.76mmol) embodiment 27a) title compound, 3.43g (12.87mmol) embodiment 27c) title compound and 6.19g (30mmol) dicyclohexylcarbodiimide under 0 ℃, be dissolved among the 40ml THF, under this temperature, stirred 2 hours stirring at room 12 hours.Add the 30ml ether, the precipitation that filtering generates.The filtrate evaporated in vacuo.The residuum silica gel column chromatography, 20: 1 wash-outs of methylene dichloride/acetone get the cream-colored solid of 5.59g, yield 48% (in the 27c compound).Calculated value: C53.08% H5.79% N9.28% S14.1 7% measured value: N-methane sulfonyl tyrosyl ammonia-4-benzyl oxide C52.93% H5.84% N9.13% S14.02% embodiment 28a)
20g (55.03mmol) embodiment 19a) title compound is dissolved among the 300ml THF, and 0 ℃ fed ammonia 3 hours down.Be evaporated to dried, the residuum methanol crystallization, the colourless platelet of 18.6g, yield: 97%.Calculated value: C58.60% H5.79% N8.04% S9.20% measured value: 2-(4-benzyloxy benzyl)-1-methane sulfonyl-1 C58.47% H5.88% N7.91% S9.05%b), 4-diaza butane
18g (51.66mmol) embodiment 28a) title compound is dissolved among the 200mlTHF, adds the THF solution of 310ml 1M diboron hexahydride under nitrogen atmosphere.Reflux 24 hours.Ice bath is cooled to 0 ℃, adds the 70ml concentrated hydrochloric acid.Reflux 5 hours.Be evaporated to dried.Residuum adds the 300ml saturated sodium carbonate solution.With dichloromethane extraction 3 times, each 100ml.Merge organic phase, dried over mgso, vacuum-evaporation is to doing.Silica gel column chromatography, 10: 1 wash-outs of methylene dichloride/ethanol get the cream-colored solid of 15.38g.Yield: 89%.Calculated value: C61.05% H6.63% N8.38% S9.59% measured value: 4-N-butoxy carbonyl-2-(4-benzyloxy benzyl)-1-methane sulfonyl-1,4 C60.91% H6.54% N8.27% S9.41%c), 7-three azepines heptan-3-ketone
15g (44.85mmol) embodiment 28b) title compound is dissolved in the 200ml chloroform, and 0 ℃ adds 5g (49.34mmol) triethylamine and 12.84g (49.34mmol) N-tertbutyloxycarbonyl-glycine-N-hydroxy-succinamide down.Stirring at room 12 hours.With cold 5% hcl as extraction agent 2 times, wash 1 time.Organic phase is through dried over mgso, and vacuum-evaporation removes to doing.Obtain the 20.51g amorphous solid, yield 93%.Calculated value: C58.64% H6.77% N8.55% S6.52% measured value: 2-(4-benzyloxy benzyl)-1-methane sulfonyl-1,4 C58.47% H6.85% N8.43% S6.41%d), 7-three azepines heptan-3-ketone
The title compound of 20g (40.68mmol) embodiment 28C is dissolved in the 100ml trifluoroacetic acid, stirring at room 5 hours.Evaporated in vacuo.Residuum is handled with the 200ml saturated sodium carbonate, chloroform extraction 3 times, each 100ml.Organic phase is through dried over sodium sulfate, and vacuum concentration obtains the 15.61g vitreous solid.Yield 98%.Calculated value: C58.29% H6.44% N10.73% S8.19% measured value: 9-chloro-2-(4-benzyloxy benzyl)-1-methane sulfonyl-1,4 C58.13% H6.60% N10.61% S8.05%e), the 7-three azepine ninth of the ten Heavenly Stems-5,8-diketone
10g (25.54mmol) embodiment 28d) title compound and 2.58g (25.54mmol) triethylamine are dissolved in the 200ml chloroform.0 ℃ drips 2.88g (25.54mmol) chloro-acetyl chloride in following 30 minutes.0 ℃ was stirred 3 hours.Be poured in the 200ml 5% cold hydrochloric acid vigorous stirring.Separate organic phase, dried over mgso, evaporated in vacuo.The residuum methanol crystallization gets the cream-colored solid of 11.36g, yield 95%.Calculated value: C53.90% H5.60% N8.98% S6.85% Cl7.58% measured value: 10-benzoyl-2-(4-benzyloxy benzyl)-1-methane sulfonyl-1 C53.80% H5.71% N8.91% S6.73% Cl7.44%f); 4; the 7-three azepines-10-sulfo-last of the ten Heavenly stems-5, the 8-diketone
5g (10.68mmol) embodiment 28e) title compound, 1.08g (10.68mmol) triethylamine and 1.48g (10.68mmol) thiobenzoic acid reflux 10 minutes in the 50ml chloroform.Evaporate to dryness, the residuum silica gel column chromatography, 15: 1 wash-outs of methylene dichloride/acetone get the cream-colored amorphous solid of 4.93g.Yield 81% calculated value: C59.03% H5.48% N7.38% S11.26% measured value: C58.87% H5.31% N7.25% S11.04% embodiment 29a) 9; 9 '-two-(2-(4-benzyloxy benzyl)-1-methane sulfonyl-1; 4,7-three azepines ninth of the ten Heavenly Stems-3-ketone)-disulphide
Under ebuillition of heated in 1 hour with 2.0gg (13.17mmol) 1,6-two chloro-3,4-dithio hexane (being dissolved in the 20ml acetonitrile) are added drop-wise to 10g (26.35mmol) embodiment 19b) title compound and 10.92g (79mmol) salt of wormwood in the 100ml acetonitrile.12 hours reflux.Filtering salt, the filtrate vacuum is to doing, and residuum is through silica gel column chromatography, and 10: 1 wash-outs of methylene dichloride/Virahol get the 2.19g yellow crystalline powder.Yield 19% (with 1,6-two chloro-3,4-dithio hexane meter).Calculated value: C54.77% H6.43% N9.58% S14.62% measured value: 6-chloro-2-(4-benzyloxy benzyl)-1-methane sulfonyl-1 C54.61% H6.35% N9.41% S14.51% embodiment 30a), own-5 ketone of 4-diaza
The embodiment 28b of 10g (25.54mmol)) title compound is dissolved in the 200ml chloroform with 3.03g (29.90mmol) triethylamine.Under 0 ℃, be added dropwise to 3.38g (29.90mmol) chloroacetyl chloride, under this temperature, stirred 2 hours.It is poured into the cold hydrochloric acid of 200ml5%, fully stirs.Separate organic phase, dried over mgso, evaporated in vacuo, the residuum recrystallizing methanol gets the 11.67g colourless crystallization.Yield 95%.Calculated value: C55.54% H5.64% N6.82% S7.80% Cl8.63% measured value: C55.38% H5.71% N6.67% S7.63% Cl8.51%b) 9; 9 '-two (2-(4-benzyloxy benzyl)-1-methane sulfonyl-1; 4,7-three azepines ninth of the ten Heavenly Stems-5-ketone)-disulphide
10g (24.34mmol) embodiment 30a) title compound, 1.52g (10mmol) cystamine and 8.29g (60mol) salt of wormwood were in 150mlTHF reflux 8 hours.Filtering salt, the filtrate evaporated in vacuo, residuum is through silica gel column chromatography, and 15: 1 wash-outs of methylene dichloride/ethanol must 2.02g be light yellow solid, yield 23% (in cystamine).Calculated value: C54.77% H6.43% N9.58% S14.62% measured value: cystamine-two-(chlor(o)acetamide) C54.61% H6.52% N9.47% S14.48% embodiment 31a)
In 02 time 10g (65.67mmol) cystamine and 13.29g (131.34mmol) triethylamine are dissolved in the 100ml chloroform, under 0 ℃ 14.38g (131.34mmol) chloroacetyl chloride are splashed into, 0 ℃ was stirred 3 hours.In solution impouring 200ml 5% cold hydrochloric acid, vigorous stirring.Organic phase is through dried over mgso, vacuum-evaporation, and a little acetone recrystallization of residuum obtains the cream-colored solid of 17.04g.Calculated value: C31.48 H4.62 N9.18 S21.01 Cl23.23% measured value: C31.27 H4.51 N9.09 S20.93 Cl23.12%b) 9; 9 '-two (2-(4-benzyloxy benzyl)-1-methane sulfonyl-1; 4,7-three azepines-ninth of the ten Heavenly Stems-6-ketone) disulphide
5g (16.38mmol) embodiment 31a) title compound 13.69g (40.95mmol) title compound, embodiment 28b) and 20.73g (150mmol) salt of wormwood reflux 8 hours in 200ml ethanol.Add the 200ml methylene dichloride, filtering salt, evaporated in vacuo filtrate, residuum is through silica gel column chromatography, and 15: 1 wash-outs of methylene dichloride/ethanol get the 4.74g vitreous solid.Yield 33%.Calculated value: C54.77% H6.43% N9.58% S14.62% measured value: 2-(4-benzyloxy benzyl)-1-methane sulfonyl-1 C54.65% H6.37% N9.41% S14.53% embodiment 32a)
5g (13.18mmol) embodiment 19b) title compound is dissolved in 50ml THF, adds 80ml 1M diboron hexahydride solution (1M is in THF).Reflux 24 hours.Be cooled to 0 ℃, add the 20ml concentrated hydrochloric acid.Reflux is 5 hours then.Solution concentration is to doing, and with the dissolving of 200ml saturated sodium carbonate solution, chloroform extraction is 5 times then, each 100ml.Merge organic phase, dried over sodium sulfate.Vacuum concentration, the residuum silica gel column chromatography, methylene dichloride/Virahol wash-out gets the 4.19g vitreous solid, yield 87%.Calculated value: C59.15% H7.45% N11.50% S8.77% measured value: C59.03% H7.28% N11.37% S8.61%b) 9; 9 '-two-(2-(4-benzyloxy benzyl)-1-methane sulfonyl-1; 4,7-three azepines ninth of the ten Heavenly Stems-8-ketone)-disulphide
4g (10.94mmol) embodiment 32a) title compound, 0.67g (3.65mmol) 2,2 '-dithio oxalic acid and 2.48g (12.04mmol) dicyclohexylcarbodiimide are dissolved among the 20mlTHF in 0 ℃, stir 3 hours under this temperature.Under room temperature, stirred 24 hours then.Add the 20ml ether, filtering precipitation, vacuum concentrated filtrate.Residuum is through silica gel column chromatography, and 15: 1 wash-outs of methylene dichloride/ethanol get the 0.99g amorphous solid, yield: 31% (in dicarboxylic acid).Calculated value: C54.77% H6.43% N9.58% S14.62% measured value: C54.58% H6.38% N9.47% S14.51%
Claims (12)
1. the compound of general formula I
V in the formula
1, V
2, V
3And V
4Independent separately represent carbonyl, CH (COOH) or-CH
2-Ji; X
1Represent hydrogen atom, the optional C that is replaced by a carboxyl, amino or thiocyano
1-C
12-alkyl or ordination number are 43,45,46,75, the metal ion Equivalent of 82 or 83 radioelement metal ion; X
2, X
3Independent separately metal ion Equivalent of thorium ionic of representing hydrogen atom or above-mentioned ordination number; N, m, p represent 0 or 1, m+n=1, R
1Represent hydrogen atom, carboxyl or-the U-Z base, U represents singly-bound, straight or branched, saturated or unsaturated C
1-C
20Alkyl, it is optional contain dimaleoyl imino, succinimido, optional by the phenyl of 1-5 fluorine atom, amino or nitro replacement ,-or two imino-s, phenylene, inferior phenoxy group, inferior phenylamino, amido, hydrazide group, carbonyl, urea groups, thioureido, thio acylamino, ester group, 1-2 Sauerstoffatom, sulphur atom and/or nitrogen-atoms, and optional 1-5 hydroxyl, sulfydryl, oxo, sulfo-, carboxyl, alkane carboxylic acid group, ester group, thiocyano and/or amino; Z represents hydrogen atom, the segment of amino acid, peptide, polynucleotide or steroidal compounds, or the optional functional group that can link to each other with amino acid, titanium, polynucleotide or steroidal thing; R
2Represent the C of straight or branched
1-C
10-alkyl, the optional carboxyl, C of containing on it
7-C
12-aralkyl, or aromatic nucleus can randomly be replaced by chlorine, bromine, thiocyano, methyl, ethyl, carboxyl and/or methoxyl group on it; R
4Represent hydrogen atom or carboxyl, or work as R
1During for hydrogen or carboxyl, then be-the U-Z base, the implication of U, Z is the same, R
3Be hydrogen atom, the metallic element ion Equivalent of aforementioned ordination number, trifluoroacetic acid base, acetoxyl, benzoyloxy, C
1-C
6-acyl group, benzoyl, glycolyl, ethanamide methyl, the optional benzoyloxy that is replaced by chlorine atom, bromine atoms or a methyl, ethyl, carboxyl and/or methoxyl group, to methoxybenzyl, ethoxyethyl, SH-protecting group,
Perhaps work as X
2, X
3Be hydrogen, X
1Be hydrogen or the optional C that replaces
1-C
12During alkyl, R
3Be formula II group
V in the formula
1, V
2, V
3, V
4, X
1, X
2, X
3, n, m, p, R
1, R
2And R
4Implication the same, V wherein
1, V
2, V
3, V
4In at least one, to too many by two be carbonyl.
2. the compound of general formula I is characterized in that, X
1, X
2, X
3Or R
3In at least 2 groups be that ordination number is 43,45,46,75,82 or 83 the isotopic metal ion Equivalent of radioactive metal.
3. according to the compound of one of top claim, it is characterized in that Z is amino acid or peptide.
4. according to the compound of one of front claim, it is characterized in that Z is polynucleotide.
5. according to the compound of one of front claim, it is characterized in that V
1And V
4Be respectively carbonyl, V
2And V
3Be respectively-CH
2-Ji and p are numeral 0.
6. according to the compound of one of front claim, it is characterized in that radioactive metal ion comprises the 99m-technetium.
7. according to the compound of one of front claim, it is characterized in that R
4Be hydrogen or carboxyl.
8. according to the compound of one of front claim, it is characterized in that R
2Be p-CH
3-C
6H
4-Ji.
9. according to the compound of one of front claim, it is characterized in that X
1, X
2And X
3Be hydrogen atom, R
3A group for formula II.
10. the medicament that contains the metal complexes of at least a general formula I, X in this metal complexes
1, X
2, X
3(or) R
3In at least 2 groups are metal ion Equivalents.
11. the metal complexes of claim 1 is used for radiodiagnosis and radiocurable purposes.
12. the medicaments preparation method of claim 10 is characterized in that, makes X among the formula I
2And X
3Be hydrogen atom, X
1Be hydrogen atom or the optional C that replaces
1-C
12The compound of-alkyl, reductive agent are dissolved in the aqueous medium, and the additive of the conventional usefulness of adding Galenicals, after randomly adding transfer ligand, salt or reactive metal oxide with required metal ion, and randomly add acceptable radioactivity carrier substance on the pharmacology, it is excessive that the title complex that adds forms agent, and optional form with its an alkali metal salt adds.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4425781.3 | 1994-07-14 | ||
| DE4425781A DE4425781A1 (en) | 1994-07-14 | 1994-07-14 | Technetium sulfonamide complexes, their use, pharmaceutical compositions containing them, and processes for the preparation of the complexes and compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1152914A true CN1152914A (en) | 1997-06-25 |
Family
ID=6523740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95194028A Pending CN1152914A (en) | 1994-07-14 | 1995-06-22 | Technetium-sulphonamide complexes, their use, pharmaceutical agents containing them, and process for producing the complexes and agents |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0770063A1 (en) |
| JP (1) | JPH10502648A (en) |
| KR (1) | KR970704682A (en) |
| CN (1) | CN1152914A (en) |
| AU (1) | AU698824B2 (en) |
| CA (1) | CA2194561A1 (en) |
| DE (1) | DE4425781A1 (en) |
| HU (1) | HUT76806A (en) |
| NO (1) | NO970140L (en) |
| WO (1) | WO1996002500A1 (en) |
| ZA (1) | ZA955896B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5028422A (en) * | 1986-05-27 | 1991-07-02 | Schering Corporation | Treatment of basal cell carcinoma intralesionally with recombinant human alpha interferon |
| EP1301474B1 (en) * | 2000-07-06 | 2008-09-10 | Array Biopharma Inc. | Tyrosine derivatives as phosphatase inhibitors |
| KR100445971B1 (en) * | 2002-04-15 | 2004-08-25 | 한국원자력연구소 | Process for labeling technetium or rhenium using borohydride exchange resin |
| SI2151250T1 (en) * | 2002-05-06 | 2014-02-28 | Endocyte, Inc. | Vitamin-Targeted imaging agents |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4980147A (en) * | 1984-06-25 | 1990-12-25 | University Of Utah Research Foundation | Radiolabeled technetium chelates for use in renal function determinations |
| DE3762624D1 (en) * | 1986-05-28 | 1990-06-13 | Mallinckrodt Inc | TECHNETIUM CHELATE FOR DETERMINING THE KIDNEY FUNCTION. |
-
1994
- 1994-07-14 DE DE4425781A patent/DE4425781A1/en not_active Withdrawn
-
1995
- 1995-06-22 HU HU9700101A patent/HUT76806A/en unknown
- 1995-06-22 JP JP8504625A patent/JPH10502648A/en active Pending
- 1995-06-22 CN CN95194028A patent/CN1152914A/en active Pending
- 1995-06-22 EP EP95924304A patent/EP0770063A1/en not_active Withdrawn
- 1995-06-22 CA CA002194561A patent/CA2194561A1/en not_active Abandoned
- 1995-06-22 KR KR1019970700193A patent/KR970704682A/en not_active Application Discontinuation
- 1995-06-22 WO PCT/EP1995/002404 patent/WO1996002500A1/en not_active Application Discontinuation
- 1995-06-22 AU AU28865/95A patent/AU698824B2/en not_active Ceased
- 1995-07-14 ZA ZA955896A patent/ZA955896B/en unknown
-
1997
- 1997-01-13 NO NO970140A patent/NO970140L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0770063A1 (en) | 1997-05-02 |
| CA2194561A1 (en) | 1996-02-01 |
| AU698824B2 (en) | 1998-11-05 |
| KR970704682A (en) | 1997-09-06 |
| HUT76806A (en) | 1997-11-28 |
| AU2886595A (en) | 1996-02-16 |
| DE4425781A1 (en) | 1996-01-18 |
| JPH10502648A (en) | 1998-03-10 |
| WO1996002500A1 (en) | 1996-02-01 |
| NO970140D0 (en) | 1997-01-13 |
| ZA955896B (en) | 1996-02-19 |
| NO970140L (en) | 1997-03-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111263747B (en) | Pharmacokinetic enhancement of difunctional chelates and uses thereof | |
| JP7449864B2 (en) | Chemical conjugates of Evans blue derivatives and their use as radiotherapy and contrast agents to target prostate cancer | |
| ES2700234T3 (en) | Marked inhibitors of prostate-specific membrane antigen (PSMA), biological evaluation and use as imaging agents | |
| CN112194651B (en) | Precursor compound of PET tracer and application thereof | |
| RU2592685C2 (en) | Radioactive labelled peptides binding to her2 | |
| CN116617420A (en) | Compound targeting fibroblast activation protein alpha, pharmaceutical composition and application | |
| CN1622830A (en) | Peptide-based compounds | |
| JP6966741B2 (en) | Radioactive labeling drug | |
| WO2019065774A1 (en) | Radioactive drug | |
| JP6164556B2 (en) | Drug for producing radiolabeled polypeptide with reduced nonspecific renal accumulation | |
| JP6661010B2 (en) | Peptide thiourea derivative, radioisotope-labeled compound containing the same, and pharmaceutical composition containing the same as active ingredient for treating or diagnosing prostate cancer | |
| TW202043288A (en) | Complex comprising ligand and ceacam5 antibody fab fragment | |
| JPH08508263A (en) | Chelating agents of the type XN-lower 1 S-lower 1 O-lower 1 for radioisotopes, their metal complexes and their use in diagnosis and therapy | |
| CN1152914A (en) | Technetium-sulphonamide complexes, their use, pharmaceutical agents containing them, and process for producing the complexes and agents | |
| IE920761A1 (en) | Chelates, their metal complexes as well as their use in¹diagnosis and treatment | |
| JPH0624972A (en) | Chelate compound and its metal complex, and preparation of diagnostic agent containing said compound, pharmaceutical drug for medical treatment of tumor and chelate compound | |
| US6488909B1 (en) | Chelating agents as well as their tricarbonyl complexes with technetium and rhenium | |
| JP2009132691A (en) | Radiolabeled reagent | |
| JP4878119B2 (en) | Enantiomerically pure (4S, 8S)-and (4R, 8R) -4-p-nitrobenzyl-8-methyl-3,6,9-triaza-3N, 6N, 9N-tricarboxymethyl-1,11-undecane Diacids and their derivatives, processes for their production and their use for the production of pharmaceuticals | |
| JP2005047821A (en) | Diagnostic or therapeutic medicine using cyclopentadienyl carbonyl group-containing radiactive compound | |
| JPH08508262A (en) | Type S3N2 chelators for radioisotopes, their metal complexes, and their diagnostic and therapeutic use | |
| TWI553017B (en) | A novel gall bladder imaging agent and its preparation method | |
| EP3643707B1 (en) | 18f-labelled compound for prostate cancer diagnosis, and use thereof | |
| US11186609B2 (en) | Method for preparing S-Bz-MAG3 as a precursor of contrast media | |
| KR100313402B1 (en) | Thioacetyldipeptide derivatives and bifunctional ligands prepared therefrom and methods for preparing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |