JPH0237345B2 - - Google Patents
Info
- Publication number
- JPH0237345B2 JPH0237345B2 JP56216075A JP21607581A JPH0237345B2 JP H0237345 B2 JPH0237345 B2 JP H0237345B2 JP 56216075 A JP56216075 A JP 56216075A JP 21607581 A JP21607581 A JP 21607581A JP H0237345 B2 JPH0237345 B2 JP H0237345B2
- Authority
- JP
- Japan
- Prior art keywords
- solution
- formula
- oxoethyl
- imino
- amino
- 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.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 33
- -1 trimethylphenyl Chemical group 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- UDLJWHHLPYMPPJ-UHFFFAOYSA-N 2-[[2-(3-bromo-2,6-diethyl-4-methylanilino)-2-oxoethyl]-(carboxymethyl)amino]acetic acid Chemical compound CCC1=CC(C)=C(Br)C(CC)=C1NC(=O)CN(CC(O)=O)CC(O)=O UDLJWHHLPYMPPJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 239000000243 solution Substances 0.000 description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 19
- 229940056501 technetium 99m Drugs 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000012153 distilled water Substances 0.000 description 14
- 210000004185 liver Anatomy 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000000941 bile Anatomy 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- DJQJFMSHHYAZJD-UHFFFAOYSA-N lidofenin Chemical compound CC1=CC=CC(C)=C1NC(=O)CN(CC(O)=O)CC(O)=O DJQJFMSHHYAZJD-UHFFFAOYSA-N 0.000 description 4
- ANOBYBYXJXCGBS-UHFFFAOYSA-L stannous fluoride Chemical compound F[Sn]F ANOBYBYXJXCGBS-UHFFFAOYSA-L 0.000 description 4
- 229960002799 stannous fluoride Drugs 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 210000000013 bile duct Anatomy 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical class OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- KWVPRPSXBZNOHS-UHFFFAOYSA-N 2,4,6-Trimethylaniline Chemical compound CC1=CC(C)=C(N)C(C)=C1 KWVPRPSXBZNOHS-UHFFFAOYSA-N 0.000 description 2
- OIXUMNZGNCAOKY-UHFFFAOYSA-N 2,6-diethyl-4-methylaniline Chemical compound CCC1=CC(C)=CC(CC)=C1N OIXUMNZGNCAOKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 210000000232 gallbladder Anatomy 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012216 imaging agent Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- MHPZZZZLAQGTHT-UHFFFAOYSA-N mebrofenin Chemical compound CC1=CC(C)=C(NC(=O)CN(CC(O)=O)CC(O)=O)C(C)=C1Br MHPZZZZLAQGTHT-UHFFFAOYSA-N 0.000 description 2
- 238000009206 nuclear medicine Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229960003330 pentetic acid Drugs 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000012217 radiopharmaceutical Substances 0.000 description 2
- 229940121896 radiopharmaceutical Drugs 0.000 description 2
- 230000002799 radiopharmaceutical effect Effects 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- 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 1
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 1
- YKYIFUROKBDHCY-ONEGZZNKSA-N (e)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical group CCO\C=C\C(=O)C(F)(F)F YKYIFUROKBDHCY-ONEGZZNKSA-N 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- IZEFTTLLQCXMCW-UHFFFAOYSA-N 2-[[2-(4-bromo-3-methylanilino)-2-oxoethyl]-(carboxymethyl)amino]acetic acid Chemical compound CC1=CC(NC(=O)CN(CC(O)=O)CC(O)=O)=CC=C1Br IZEFTTLLQCXMCW-UHFFFAOYSA-N 0.000 description 1
- WNIDXAKKFOKNEF-UHFFFAOYSA-N 2-[carboxymethyl-[2-(2,6-diethylanilino)-2-oxoethyl]amino]acetic acid Chemical compound CCC1=CC=CC(CC)=C1NC(=O)CN(CC(O)=O)CC(O)=O WNIDXAKKFOKNEF-UHFFFAOYSA-N 0.000 description 1
- JMCYMWPKZIDMHK-UHFFFAOYSA-N 2-[carboxymethyl-[2-(4-iodoanilino)-2-oxoethyl]amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(=O)NC1=CC=C(I)C=C1 JMCYMWPKZIDMHK-UHFFFAOYSA-N 0.000 description 1
- ZGXLCJXTSSBXPZ-UHFFFAOYSA-N 2-[carboxymethyl-[2-oxo-2-(2,4,6-trimethylanilino)ethyl]amino]acetic acid Chemical compound CC1=CC(C)=C(NC(=O)CN(CC(O)=O)CC(O)=O)C(C)=C1 ZGXLCJXTSSBXPZ-UHFFFAOYSA-N 0.000 description 1
- MVLMPTBHZPYDBZ-UHFFFAOYSA-N 3-bromo-2,4,6-trimethylaniline Chemical compound CC1=CC(C)=C(Br)C(C)=C1N MVLMPTBHZPYDBZ-UHFFFAOYSA-N 0.000 description 1
- FCFLPZAAPZHJKJ-UHFFFAOYSA-N 3-bromo-2,6-diethyl-4-methylaniline Chemical compound CCC1=CC(C)=C(Br)C(CC)=C1N FCFLPZAAPZHJKJ-UHFFFAOYSA-N 0.000 description 1
- GRXMMIBZRMKADT-UHFFFAOYSA-N 3-bromo-4-methylaniline Chemical compound CC1=CC=C(N)C=C1Br GRXMMIBZRMKADT-UHFFFAOYSA-N 0.000 description 1
- RRUDMHNAMZFNEK-UHFFFAOYSA-N 3-iodo-4-methylaniline Chemical compound CC1=CC=C(N)C=C1I RRUDMHNAMZFNEK-UHFFFAOYSA-N 0.000 description 1
- MMEGELSFOYDPQW-UHFFFAOYSA-N 4-bromo-3-methylaniline Chemical compound CC1=CC(N)=CC=C1Br MMEGELSFOYDPQW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- ZLIRJJJHZCGEDV-UHFFFAOYSA-N CC1=C(C=C(C(=C1)C)C)NC(=O)CN(CC(=O)O)CC(=O)O Chemical compound CC1=C(C=C(C(=C1)C)C)NC(=O)CN(CC(=O)O)CC(=O)O ZLIRJJJHZCGEDV-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZOKXTWBITQBERF-AKLPVKDBSA-N Molybdenum Mo-99 Chemical compound [99Mo] ZOKXTWBITQBERF-AKLPVKDBSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 238000004159 blood analysis Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GHAFORRTMVIXHS-UHFFFAOYSA-L bromosulfophthalein sodium Chemical compound [Na+].[Na+].C1=C(S([O-])(=O)=O)C(O)=CC=C1C1(C=2C=C(C(O)=CC=2)S([O-])(=O)=O)C(C(Br)=C(Br)C(Br)=C2Br)=C2C(=O)O1 GHAFORRTMVIXHS-UHFFFAOYSA-L 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229950009740 molybdenum mo-99 Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940023462 paste product Drugs 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960001734 sulfobromophthalein Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- IUTCEZPPWBHGIX-UHFFFAOYSA-N tin(2+) Chemical compound [Sn+2] IUTCEZPPWBHGIX-UHFFFAOYSA-N 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- 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
- A61K2123/00—Preparations for testing in vivo
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明はＮ−置換ジ酢酸類、更に詳しくは式、
〔式中、R1およびR4はそれぞれ独立して水素、
メチルまたはエチル、R2とR3の一方は炭素数１
〜４のアルキルで、他方は臭素またはヨウ素、お
よびｎは０である。〕
を有する化合物またはその医薬的に許容しうる水
溶性塩に関する。式［］の化合物またはその水
溶性塩は還元剤の存在下でテクネチウム−99ｍと
好適に複合する。式〔〕においておよび本明細
書を通じて、記号は前記と同意義である。
テクネチウム−99mと式〔〕の化合物との複
合体類は、肝胆管系の外的映像形成（imaging）
に有用である。かかる複合体は良好な特異性（即
ち、哺乳動物に注射した場合、複合体の多くは肝
臓を通つて胆汁に入る）を有しており、また十分
な胆管容量を考慮すれば肝臓から胆汁への急速な
輸送を示す。
脳を除いて肝臓は核医学手順により最も頻繁に
検査される器管である。これらの研究のほとんど
は、クツペル細胞により有効にトラツプされる
Tc−99m・イオウコロイドなどの標識粒子の静
脈内投与を付随的に伴う。このようにして得られ
る診断情報は、肝臓形態学やクツペル細胞機能の
研究に有用である。これらの研究に最適な作用剤
としては、健康なクツペル細胞への急速で排他的
な吸収（uptake）を有し、生体内分解性で非毒
性のものである。
放射性核種研究はまた、肝細胞（hepatocyte）
機能および胆管開存性（胆のう機能を含む）を測
定するのにも用いられる。これらの研究の最適作
用剤は、肝細胞による急速で排他的な吸収、急速
な肝内移行、および胆管系への迅速な***を有す
るものである。患者の放射線量を制限しながら、
最大限の診断情報を得るのに高度の特異性が要求
される。最大肝臓濃度への時間（tnax）および
tnax濃度の50％に低下する肝臓濃度の時間（t50）
はいずれも、研究に必要な時間を縮小するため短
かくなければならない。このことは、長時間の間
不動化しておくことができない患者にとつて重要
である。より短い研究時間は、映像形成機器の使
用を最大限にしながら一定期間内で処理できる患
者数の増大を意味する。短いt50もまた、胆汁内
の放射能と肝臓内の放射能との比の増大を意味
し、これによつて肝臓からの肝内管を分解して、
映像および結果的診断の質を改良する。
最近まで、核医学胆管機能研究のほとんどはＩ
−131ローズベンガルまたはＩ−131ブロモスルホ
フタレインを用いて遂行されていた。Ｉ−131ロ
ーズベンガルは通常、肝臓機能作用剤を比較する
ための標準であるが、その光子エネルギーはガン
マカメラ映像形成（gamma camera imaging）
に最適でなく、患者の非診断性ベータ放射線への
照射は、安全に投与しうる用量を制限する。従つ
て、映像分解（resolution）および診断情報は制
限される。1974年のチユビス（Tubis）らによる
Tc−99mペニシラミンの開発（サブラマニアン
（Subramanian）ら著「Radiopharmaceuticals」
（ザ・ソサイアテイ・オブ・ニユークリア・メデ
イスン・インコーポレイテツド、ニユーヨーク、
1975年、55〜62頁）参照）は、ヨウ素−131標識
（label）の制限を解消し、テクネチウム−99m標
識肝胆管作用剤の調査興味を活気づける重要なス
テツプであつた。今日までに開発されてきたテク
ネチウム−99m標識作用剤の最も有用なものは、
Ｎ−置換イミジノ酢酸類（ヘパトイミジノ酢酸
類：HIDA′s）である。ロベーグ（Loberg）らは
米国特許第4017596において、就中、外的器管映
像形成用のテクネチウム−99mのキレート薬およ
び置換イミノジ酢酸の使用を開示している。エツ
ケルマン（Eckelman）らは、米国特許第
3725295においてテクネチウム−99mによるジエ
チレントリアミンペンタ酢酸（DTPA）の標識
法を開示している。
上記文献に開示された各種HIDA誘導体は、
式：
で表わすことができる。
ここで討議される類似化合物としては、２，６
−ジメチル誘導体（ロベーグらの米国特許第
4017596参照）、２，６−ジエチル、２，６−ジイ
ソプロピル、２−ブトキシ、４−ブトキシ、４−
ブチル、４−イソプロピル、４−エトキシおよび
４−ヨード誘導体（ウイストウ（Wistow）ら著
「Radiology」（128巻、793〜794頁、1978年）参
照）、２，３−ジメチル、２，４−ジメチル、２，
５−ジメチル、３，４−ジメチルおよび３，５−
ジメチル誘導体（バン・ウイツク（Van Wyk）
ら著「Eur.J.Nucl.Med.」（４巻、445〜448頁、
1979年）参照）、および２，４，６−トリ置換誘
導体（ここで、置換基の少なくとも２つは炭素数
１〜４のアルキルで、３つ目の置換基は水素また
は炭素数１〜４のアルキルであり、また各置換基
を合わせると少なくとも３個の炭素を含有する。
ベルギー特許第855107参照）、並びに２，６−ジ
メチル、２，６−ジエチル、２，６−ジイソプロ
ピル、４−メチル、４−エチル、４−イソプロピ
ル、４−ｎ−ブチル、４−ｎ−ペンチル、４−ｔ
−ブチル、４−フエニル、４−メトキシ、３，５
−ジメチル、２，４，６−トリメチル、２，４，
５−トリメチル、４−フルオロ、２，４−ジフル
オロ、２，５−ジフルオロおよび２，３，４，
５，６−ペンタフルオロ誘導体（モルテン
（Molten）ら著「3rd Int.Symp.Radiopharm.
Chem.」（ミズリー州セントロイス、1980年６月）
参照）が包含される。また、フイールズ
（Fields）ら著「Journal of Labelled
Compounds and Radiopharmaceuticals」（XV
巻、387〜399頁、1978年）には、Ｎ−（２−フエ
ネチルカルバモイルメメチル）イミノジ酢酸が開
示されている。
バン・ウイツクら著「Eur.Nucl.Med.」（４巻、
445〜448頁、1979年）によれば、ジメチルHIDA
誘導体を用いるその作用において、置換基の立体
効果は胆汁吸収（biliary uptake）に重要である
ことが示されている。チオテリス（Chiotellis）
ら著「Int.J.Nucl.Med.Biol.」（７巻、１〜７頁、
1980年）によれば、４−ブチルHIDA化合物を用
いる作用において、置換基の分子大きさは胆汁吸
収に重要であることが示されている。
本発明の式〔〕の化合物類およびそれらの塩
類は、テクネチウム−99mで標識することがで
き、次いで肝胆管系を映像形成する（imaging）
ため患者に静脈内投与することができる。式
〔〕の化合物類およびそれらの塩類の放射線標
識は、当該分野で周知の手順を用いて遂行するこ
とができる。好ましい手順において、過テクネチ
ウム酸ナトリウム水溶液（Na99mTcO4）の形状
のテクネチウム−99mを、還元剤および式〔〕
の化合物またはその塩とコンバインする。上記三
成分の混合順序は臨界的ではないが、最初に還元
剤と式〔〕の本発明化合物をコンバインするこ
とが最も好ましい。次に、この組成物（非放射性
組成物）を、放射化学者、技術者、放射製薬者、
医者およびその他に供給して、正に使用前のテク
ネチウム−99mで標識することができる。
第一錫イオンは、好ましい還元剤である。第一
錫還元剤の具体例は、塩化第一錫および弗化第一
錫である。
過テクネチウム酸ナトリウムの水溶液形状のテ
クネチウム−99mは、慣用的に塩水で溶出され
る、商業上入手可能なモリブデン−99／テクネチ
ウム−99m発生剤から容易に得ることができる。
式〔〕の本発明化合物は、出発物質としてニ
トリロトリ酢酸、無水酢酸、および式：
を有するアミン誘導体を用いて製造することがで
きる。先ず、ニトリロトリ酢酸と無水酢酸を反応
させて無水ニトリロトリ酢酸を得、次いでこれを
式〔〕のアミンと反応させて式〔〕の対応化
合物を得る。反応体が化学量論量で存在する場
合、反応は最も容易に進行する。
式〔〕の化合物類は、当該分野で認められて
いる手順を用いて医薬的に許容しうる水溶性塩類
に変換することができる。好ましい塩類は、アル
カリ金属塩類およびアルカリ土類金属塩類であ
る。
テクネチウム−99mと複合する、式〔〕の化
合物類（およびその塩類）を含む組成物は、当該
分野で認められている手順を用いて製造すること
ができる。例えば、先ず式〔〕の化合物（また
はその塩）を塩基（例えば水酸化ナトリウム）に
溶解して、PH約６〜７溶液を得ることにより、
“ウエツト・キツト（wet kit）”を製造しうる。
この溶液に塩酸中の還元剤（例えば弗化第一錫）
の酸性溶液を加える。水を加えて所望容量にする
ことができる。この溶液にテクネチウム−99m
（好ましくは過テクネチウム酸ナトリウム水溶液）
を加えることができる。凍結乾燥キツトは、テク
ネチウム−99mの添加に先立ち溶液を凍結乾燥す
る以外は、上述の手順を用いて製造することがで
きる。凍結乾燥物質は、不活性雰囲気中で貯蔵さ
れてよい。
次に示す実施例は、本発明の特別な実施態様例
である。
実施例 １
２，2′−〔〔２−〔（３−ブロモ−２，４，６−ト
リメチルフエニル）アミノ〕−２−オキソエチ
ル〕イミノ〕ビス酢酸の製造：−
(A) ３−ブロモ−２，４，６−トリメチルアニリ
ンの製造：−
濃塩酸（80ml）を氷−水浴中で５℃に冷却す
る。激しく撹拌しながら、２，４，６−トリメ
チルアニリン（13.5ｇ）を20分間にわたつて添
加し、その間温度を15℃以下に保つ。かかる濃
厚スラリーを３℃に冷却し、80mlの濃塩酸中の
16.8ｇの臭素を25分間にわたつて添加する。ス
ラリーを水浴で１時間加熱し、次いで氷浴で１
時間冷却する。次に反応混合物を過し、塩を
50ml部の冷蒸留水で３回洗う。乾燥後、粗生成
物を600mlの蒸留水に溶解し、3.0ｇのダルコ
（Darco）で処理し、ハイフローベツド
（Hyflo−bed）にて過し、溶液を得る。濃水
酸化アンモニウムで中和して乳白色溶液を得、
これを10℃に冷却すると生成物が固化する。約
16時間冷却（refrigeration）後、黄褐色生成物
を取し、冷蒸留水で洗い、減圧下約16時間乾
燥して12.0ｇの表記化合物（融点34.0〜35.0℃）
を得る。
(B) ２，2′−〔〔２−〔（３−ブロモ−２，４，６−
トリメチルフエニル）アミノ〕−２−オキソエ
チル〕イミノ〕ビス酢酸の製造：−
水分を除去（CaSO4乾燥チユーブ）した、ピ
リジン（分子篩上で乾燥）中の9.56ｇのニトリ
ロトリ酢酸の懸濁液を調製し、50℃に加熱す
る。これに無水酢酸（5.11ｇ）を滴下する。反
応混合物は透明化し、これを100℃に加熱する。
この温度を40分間維持した後、反応混合物を55
℃に冷却し、25mlの乾燥ピリジン中の10.7ｇの
３−ブロモ−２，４，６−トリメチルアニリン
の溶液をゆつくりと加える。反応系を100℃に
加熱し、この温度で1.5時間後溶液を氷浴にて
冷却する。反応混合物を回転エバポレータで蒸
発させて半固体とし、これを10％Ｗ／Ｖ水酸化
ナトリウム125mlに溶解する。次いで、かかる
塩基性層を100ml部の塩化メチレンで２回抽出
する。塩基性層に蒸留水（100ml）を加え、次
いで濃塩酸でPH３とし沈殿物を得る。約16時間
冷却後、粗生成物を取し、冷蒸留水で洗い、
減圧下40℃で乾燥する。粗生成物を60％エタノ
ール水溶液100mlに溶解し、3.0ｇのダルコで処
理し、ハイフローベツドで予熱過して溶液を
得る。結晶が沈殿し、これを過し、25ml部の
エタノール50％水溶液で３回洗い、減圧下40℃
で乾燥する。かかる反応によつて9.1ｇの表記
化合物が収得される。融点198〜200℃（分解）。
実施例 ２
２，2′−〔〔２−〔（３−ブロモ−２，６−ジエチ
ル−４−メチルフエニル）アミノ〕−２−オキ
ソエチル〕イミノ〕ビス酢酸の製造：−
(A) ３−ブロモ−２，６−ジエチル−４−メチル
アニリンの製造：−
濃HCl（10ml）を氷−水浴で５℃に冷却し、
1.63ｇの２，６−ジエチル−４−メチルアニリ
ンを滴下してスラリーを得る。10mlの濃HClと
共に臭素（1.59ｇ）を30分にわたつて滴下す
る。反応系を3.75時間撹拌せしめ、25mlの蒸留
水を加える。1.0時間冷却後、反応混合物を
過し、25mlの冷蒸留水で２回洗う。減圧下で約
16時間乾燥後、粗固体（2.3ｇ）を100mlの10％
NaOHに溶解し、150ml部および100ml部の塩
化メチレンで抽出する。硫酸ナトリウム上で乾
燥後、塩化メチレン溶液を回転エバポレータで
蒸発させて1.9ｇの粗生成物とする。
(B) ２，2′−〔〔２−〔（３−ブロモ−２，６−ジエ
チル−４−メチルフエニル）アミノ〕−２−オ
キソエチル〕イミノ〕ビス酢酸の製造：−
15mlの乾燥ピリジン（分子篩上で乾燥）中の
1.34ｇのニトリロトリ酢酸のスラリーを調製
し、46℃に加熱する。無水酢酸（0.72ｇ）を加
え（１mlピリジンリンス）、溶液を100℃に加熱
する。0.5時間加熱後、溶液を46℃に冷却せし
め、６mlのピリジン中の1.7ｇの粗３−ブロモ
−２，６−ジエチル−４−メチルアニリンの溶
液をゆつくりと加える。溶液を100℃で２時間
加熱し、冷却し、回転エバポレータで蒸発させ
てペースト生成物とする。生成物を２mlの10％
水酸化ナトリウムに溶解し、得られる溶液を25
ml部の塩化メチレンで２回抽出する。水溶液を
50mlの蒸留水で希釈し、濃HClでPH3.0に中和
し、約16時間冷却する。過して固体を得、こ
れを減圧下60℃で３時間乾燥して1.4ｇの粗生
成物を得る。25mlの50％エタノールより再結晶
して1.04ｇの針状結晶（融点194.5〜195.5℃）
を得る。
実施例 ３
２，2′−〔〔２−〔（３−ヨード−４−メチルフエ
ニル）アミノ〕−２−オキソエチル〕イミノ〕
ビス酢酸の製造：−
40mlの乾燥ピリジン（分子篩上で乾燥）中の
4.78ｇのニトリロトリ酢酸のスラリーを60℃に加
熱する。無水酢酸（2.55ｇ）をゆつくりと加え、
溶液を100℃に加熱する。0.5時間加熱後、溶液を
40℃に冷却し、20mlの乾燥ピリジン中の5.8ｇの
３−ヨード−４−メチルアニリンの溶液を25分に
わたつて加える。溶液を100℃で1.0時間加熱す
る。反応系を冷却し、回転エバポレータで蒸発さ
せて残留物とし、これを65mlの水酸化ナトリウム
に溶解する。この溶液を50ml部の塩化メチレンで
２回抽出し、100mlの蒸留水で希釈し、濃HClで
PH3.2に中和する。粗生成物を約16時間冷却し、
過し、50ml部の蒸留水で２回洗い、減圧下40℃
で乾燥する。粗生成物（8.0ｇ）をダルコ処理後
再結晶して、5.7ｇの生成物を収得する。融点
213.5〜215.0℃（分解）
実施例 ４
２，2′−〔〔２−〔（４−ブロモ−３−メチルフエ
ニル）アミノ〕−２−オキソエチル〕イミノ〕
ビス酢酸の製造：−
80mlの乾燥ピリジン（分子篩上で乾燥）中の
9.56ｇのニトリロトリ酢酸のスラリーを55℃に加
熱する。無水酢酸（7.66ｇ）を加え、溶液を100
℃に加熱する。0.5時間加熱後、溶液を55℃に冷
却し、9.30ｇの４−ブロモ−３−メチルアニリン
を５mlピリジンリンスと共に加える。溶液を100
℃で1.0時間加熱する。反応系を冷却し、回転エ
バポレータで蒸発させてペースト固体とし、これ
を120mlの水酸化アンモニウム水溶液（濃水酸化
アンモニウム30ml／蒸留水90ml）に溶解する。透
明褐色溶液を100ml部の塩化メチレンで２回抽出
し、35mlの濃HClでPH３に中和する。白色固体を
取し、25ml部の冷蒸留水で３回洗い、減圧下60
℃で2.75時間乾燥する。粗生成物（12.9ｇ）を
360mlの50％エタノールより再結晶して、9.85ｇ
の生成物（融点206.5〜209.0℃）を得る。
実施例 ５
２，2′−〔〔２−〔（３−ブロモ−４−メチルフエ
ニル）アミノ〕−２−オキソエチル〕イミノ〕
ビス酢酸の製造：−
40ml中の乾燥ピリジン（分子篩上で乾燥）中の
4.78ｇのニトリロトリ酢酸のスラリーを調製し、
50℃に加熱する。無水酢酸（2.55ｇ）をゆつくり
と加え、溶液を100℃に加熱する。0.5時間加熱
後、溶液を42℃に冷却し、５mlのピリジン中の
4.81ｇの３−ブロモ−４−メチルアニリンをゆつ
くりと加える。溶液を100℃に加熱する。2.0時間
加熱後、反応系を冷却し、回転エバポレータで蒸
発させる。この物質を75mlの10％水酸化ナトリウ
ムに溶解し、50ml部の塩化メチレンで２回抽出す
る。水性部を100mlの蒸留水で希釈し、濃HClで
PH3.2に中和し、一夜約16時間冷却する。反応系
を過し、冷蒸留水で洗う。減圧下60℃で３時間
乾燥後、7.14ｇの粗生成物を得る（融点206.0〜
208.0℃）。150mlの75％エタノールより再結晶し
て6.4ｇの固体（融点209.0〜210.0℃）を得る。
実施例 ６
テクネチウム−99mと複合する配合物の調製：
−
下記表に、式〔〕の化合物と弗化第一錫還元
剤の模範配合例を示す。リガンド（配位子）を
0.46M−水酸化ナトリウムに溶解して最終PH約６
〜7.5の溶液を得ることにより、各種配合物を調
製する。これに6M−塩酸中の弗化第一錫の70
mg／ml溶液0.01mlを加え、注射用水で容量をmlと
する。以下に示す表の配合物は、リガンド：錫＝
150：１の好ましいモル比を有する。
The present invention relates to N-substituted diacetic acids, more specifically, the formula: [In the formula, R 1 and R 4 are each independently hydrogen,
Methyl or ethyl, one of R 2 and R 3 has 1 carbon number
-4 alkyl, the other being bromine or iodine, and n is 0. ] or a pharmaceutically acceptable water-soluble salt thereof. The compound of formula [] or a water-soluble salt thereof is preferably complexed with technetium-99m in the presence of a reducing agent. In formula [] and throughout this specification, the symbols have the same meanings as above. Complexes of technetium-99m and the compound of formula [] are used for external imaging of the hepatobiliary system.
It is useful for Such conjugates have good specificity (i.e., when injected into mammals, much of the conjugate enters the bile through the liver) and, given sufficient bile duct capacity, can pass from the liver to the bile. indicates rapid transport of Other than the brain, the liver is the organ most frequently examined by nuclear medicine procedures. Most of these studies show that Kutzpel cells are effectively trapped.
Concomitantly involves intravenous administration of labeled particles such as Tc-99m/sulfur colloid. The diagnostic information thus obtained is useful for studies of liver morphology and Kutzpel cell function. The agents of choice for these studies are those that have rapid and exclusive uptake into healthy Kutzpel cells, are biodegradable, and are non-toxic. Radionuclide studies have also shown that liver cells (hepatocytes)
It is also used to measure function and bile duct patency (including gallbladder function). The agents of choice for these studies are those with rapid and exclusive absorption by hepatocytes, rapid intrahepatic translocation, and rapid excretion into the biliary system. while limiting patient radiation dose.
A high degree of specificity is required to obtain maximum diagnostic information. Time to maximum liver concentration (t nax ) and
Time for liver concentration to fall to 50% of tnax concentration ( t50 )
Both must be short to reduce the time required for research. This is important for patients who cannot remain immobile for long periods of time. Shorter study times mean an increased number of patients can be processed in a given period of time while maximizing the use of imaging equipment. A short t 50 also means an increased ratio of radioactivity in the bile to radioactivity in the liver, thereby dissolving the intrahepatic ducts from the liver and
Improve the quality of images and resulting diagnosis. Until recently, most of the nuclear medicine bile duct function studies were conducted using I.
-131 Rose Bengal or I-131 Bromosulfophthalein. I-131 Rose Bengal is typically the standard for comparing liver function agents, but its photon energy is
Exposure of patients to non-diagnostic beta radiation limits the doses that can be safely administered. Therefore, video resolution and diagnostic information is limited. In 1974, Tubis et al.
Development of Tc-99m penicillamine (Subramanian et al., Radiopharmaceuticals)
(The Society of New York Medicine, Inc., New York,
(1975, pp. 55-62) was an important step in overcoming the limitations of the iodine-131 label and reinvigorating research interest in technetium-99m-labeled hepatobiliary agents. The most useful technetium-99m labeled agents developed to date are:
N-substituted imidinoacetic acids (hepatoimidinoacetic acids: HIDA's). Loberg et al., in US Pat. No. 4,017,596, disclose, among other things, the use of technetium-99m chelators and substituted iminodiacetic acids for external organ imaging. Eckelman et al., U.S. Pat.
3725295 discloses a method for labeling diethylenetriaminepentaacetic acid (DTPA) with technetium-99m. Various HIDA derivatives disclosed in the above documents are:
formula: It can be expressed as Similar compounds discussed here include 2,6
-dimethyl derivatives (U.S. patent no.
4017596), 2,6-diethyl, 2,6-diisopropyl, 2-butoxy, 4-butoxy, 4-
Butyl, 4-isopropyl, 4-ethoxy and 4-iodo derivatives (see Wistow et al., Radiology, Vol. 128, pp. 793-794, 1978), 2,3-dimethyl, 2,4-dimethyl ,2,
5-dimethyl, 3,4-dimethyl and 3,5-
Dimethyl derivatives (Van Wyk)
“Eur.J.Nucl.Med.” (vol. 4, pp. 445-448,
(1979)) and 2,4,6-trisubstituted derivatives (where at least two of the substituents are C1-C4 alkyl and the third substituent is hydrogen or C1-C4 alkyl), and each substituent group together contains at least 3 carbons.
(see Belgian Patent No. 855107) and 2,6-dimethyl, 2,6-diethyl, 2,6-diisopropyl, 4-methyl, 4-ethyl, 4-isopropyl, 4-n-butyl, 4-n-pentyl, 4-t
-butyl, 4-phenyl, 4-methoxy, 3,5
-dimethyl, 2,4,6-trimethyl, 2,4,
5-trimethyl, 4-fluoro, 2,4-difluoro, 2,5-difluoro and 2,3,4,
5,6-pentafluoro derivatives (Molten et al., “3rd Int.Symp.Radiopharm.
Chem.” (St. Lois, Missouri, June 1980)
References) are included. In addition, “Journal of Labeled” by Fields et al.
"Compounds and Radiopharmaceuticals" (XV
Vol. 387-399, 1978) discloses N-(2-phenethylcarbamoylmemethyl)iminodiacetic acid. “Eur.Nucl.Med.” by Van Uytsk et al. (4 volumes,
445-448, 1979), dimethyl HIDA
In its work with derivatives, steric effects of substituents have been shown to be important for biliary uptake. Chiotellis
“Int.J.Nucl.Med.Biol.” (vol. 7, pages 1-7,
(1980), it has been shown that the molecular size of the substituent is important for bile absorption when working with 4-butyl HIDA compounds. Compounds of formula [] and their salts of the present invention can be labeled with technetium-99m and then imaged the hepatobiliary system.
Therefore, it can be administered intravenously to patients. Radiolabeling of compounds of formula [] and their salts can be accomplished using procedures well known in the art. In a preferred procedure, technetium-99m in the form of an aqueous sodium pertechnetate solution (Na99mTcO 4 ) is combined with a reducing agent and the formula
or its salt. Although the order of mixing the above three components is not critical, it is most preferred to first combine the reducing agent and the compound of the present invention of formula []. Next, this composition (non-radioactive composition) can be used by radiochemists, engineers, radiopharmaceutics, etc.
It can be supplied to doctors and others and labeled with technetium-99m just before use. Stannous ion is a preferred reducing agent. Specific examples of stannous reducing agents are stannous chloride and stannous fluoride. Technetium-99m in the form of an aqueous solution of sodium pertechnetate can be readily obtained from commercially available molybdenum-99/technetium-99m generators that are conventionally eluted with brine. The compound of the present invention of the formula [] contains nitrilotriacetic acid, acetic anhydride as a starting material, and the formula: It can be produced using an amine derivative having the following. First, nitrilotriacetic acid and acetic anhydride are reacted to obtain nitrilotriacetic anhydride, which is then reacted with an amine of formula [] to obtain the corresponding compound of formula []. The reaction proceeds most easily when the reactants are present in stoichiometric amounts. Compounds of formula [] can be converted to pharmaceutically acceptable water-soluble salts using art-recognized procedures. Preferred salts are alkali metal salts and alkaline earth metal salts. Compositions containing compounds of formula [] (and salts thereof) in complex with technetium-99m can be prepared using art-recognized procedures. For example, by first dissolving the compound of formula [] (or its salt) in a base (e.g. sodium hydroxide) to obtain a solution with a pH of about 6 to 7,
A "wet kit" can be manufactured.
Add a reducing agent (e.g. stannous fluoride) in hydrochloric acid to this solution.
Add an acidic solution of Water can be added to make up the desired volume. Technetium-99m is added to this solution.
(preferably sodium pertechnetate aqueous solution)
can be added. A lyophilization kit can be made using the procedure described above, except that the solution is lyophilized prior to the addition of technetium-99m. Lyophilized materials may be stored in an inert atmosphere. The following examples are specific embodiments of the invention. Example 1 Production of 2,2'-[[2-[(3-bromo-2,4,6-trimethylphenyl)amino]-2-oxoethyl]imino]bisacetic acid: - (A) 3-bromo- Preparation of 2,4,6-trimethylaniline: - Concentrated hydrochloric acid (80 ml) is cooled to 5°C in an ice-water bath. With vigorous stirring, 2,4,6-trimethylaniline (13.5 g) is added over 20 minutes while maintaining the temperature below 15°C. The thick slurry was cooled to 3°C and dissolved in 80ml of concentrated hydrochloric acid.
Add 16.8 g of bromine over 25 minutes. Heat the slurry in a water bath for 1 hour, then in an ice bath for 1 hour.
Cool for an hour. Then filter the reaction mixture and remove the salt.
Wash three times with 50 ml portions of cold distilled water. After drying, the crude product is dissolved in 600 ml of distilled water, treated with 3.0 g of Darco and filtered through a Hyflo-bed to obtain a solution. Neutralize with concentrated ammonium hydroxide to obtain a milky white solution;
When this is cooled to 10°C, the product solidifies. about
After refrigeration for 16 hours, the yellow-brown product was taken, washed with cold distilled water, and dried under reduced pressure for about 16 hours to yield 12.0 g of the title compound (melting point 34.0-35.0°C).
get. (B) 2,2'-[[2-[(3-bromo-2,4,6-
Preparation of trimethylphenyl)amino]-2-oxoethyl]imino]bisacetic acid: - Prepare a suspension of 9.56 g of nitrilotriacetic acid in pyridine (dried over molecular sieves), with moisture removed (CaSO 4 dry tube) and heat to 50℃. Acetic anhydride (5.11 g) was added dropwise to this. The reaction mixture becomes clear and is heated to 100°C.
After maintaining this temperature for 40 min, the reaction mixture was
Cool to 0.degree. C. and slowly add a solution of 10.7 g of 3-bromo-2,4,6-trimethylaniline in 25 ml of dry pyridine. The reaction system is heated to 100° C. and after 1.5 hours at this temperature the solution is cooled in an ice bath. The reaction mixture is evaporated on a rotary evaporator to a semi-solid, which is dissolved in 125 ml of 10% W/V sodium hydroxide. The basic layer is then extracted twice with 100 ml portions of methylene chloride. Add distilled water (100 ml) to the basic layer, then adjust the pH to 3 with concentrated hydrochloric acid to obtain a precipitate. After cooling for about 16 hours, the crude product was taken and washed with cold distilled water.
Dry at 40°C under reduced pressure. The crude product was dissolved in 100 ml of 60% ethanol aqueous solution, treated with 3.0 g of Dalco, and preheated in a high flow bed to obtain a solution. Crystals were precipitated, filtered, washed three times with 25 ml portions of 50% aqueous ethanol solution, and heated at 40°C under reduced pressure.
Dry with. The reaction yields 9.1 g of the title compound. Melting point 198-200℃ (decomposition). Example 2 Production of 2,2'-[[2-[(3-bromo-2,6-diethyl-4-methylphenyl)amino]-2-oxoethyl]imino]bisacetic acid: - (A) 3-bromo- Preparation of 2,6-diethyl-4-methylaniline: - Concentrated HCl (10 ml) was cooled to 5°C in an ice-water bath;
1.63 g of 2,6-diethyl-4-methylaniline is added dropwise to obtain a slurry. Bromine (1.59 g) is added dropwise over 30 minutes with 10 ml of concentrated HCl. The reaction was stirred for 3.75 hours and 25 ml of distilled water was added. After cooling for 1.0 hour, the reaction mixture is filtered and washed twice with 25 ml of cold distilled water. Approximately under reduced pressure
After drying for 16 hours, the crude solid (2.3 g) was added to 100 ml of 10%
Dissolve in NaOH and extract with 150 ml and 100 ml parts of methylene chloride. After drying over sodium sulfate, the methylene chloride solution is evaporated on a rotary evaporator to give 1.9 g of crude product. (B) Preparation of 2,2'-[[2-[(3-bromo-2,6-diethyl-4-methylphenyl)amino]-2-oxoethyl]imino]bisacetic acid: - 15 ml of dry pyridine (on molecular sieves) dry) in
A slurry of 1.34 g of nitrilotriacetic acid is prepared and heated to 46°C. Acetic anhydride (0.72 g) is added (1 ml pyridine rinse) and the solution is heated to 100°C. After heating for 0.5 hour, the solution is cooled to 46 DEG C. and a solution of 1.7 g of crude 3-bromo-2,6-diethyl-4-methylaniline in 6 ml of pyridine is slowly added. The solution is heated to 100° C. for 2 hours, cooled and evaporated on a rotary evaporator to a paste product. 10% of the product in 2 ml
Dissolve in sodium hydroxide and make the resulting solution 25
Extract twice with ml portions of methylene chloride. aqueous solution
Dilute with 50 ml of distilled water, neutralize to pH 3.0 with concentrated HCl, and cool for about 16 hours. A solid was obtained by filtration, which was dried under reduced pressure at 60° C. for 3 hours to obtain 1.4 g of crude product. Recrystallize from 25ml of 50% ethanol to obtain 1.04g of needle-shaped crystals (melting point: 194.5-195.5℃)
get. Example 3 2,2′-[[2-[(3-iodo-4-methylphenyl)amino]-2-oxoethyl]imino]
Preparation of bisacetic acid: - in 40 ml of dry pyridine (dried over molecular sieves)
Heat a slurry of 4.78 g of nitrilotriacetic acid to 60°C. Slowly add acetic anhydride (2.55g),
Heat the solution to 100 °C. After heating for 0.5 h, the solution
Cool to 40° C. and add a solution of 5.8 g of 3-iodo-4-methylaniline in 20 ml of dry pyridine over 25 minutes. Heat the solution at 100 °C for 1.0 h. The reaction is cooled and evaporated on a rotary evaporator to a residue, which is dissolved in 65 ml of sodium hydroxide. This solution was extracted with two 50 ml portions of methylene chloride, diluted with 100 ml of distilled water, and extracted with concentrated HCl.
Neutralizes to PH3.2. Cool the crude product for about 16 hours,
Filter, wash twice with 50ml portions of distilled water, and store at 40°C under reduced pressure.
Dry with. The crude product (8.0 g) is recrystallized after Dalco treatment to obtain 5.7 g of product. melting point
213.5-215.0℃ (decomposition) Example 4 2,2'-[[2-[(4-bromo-3-methylphenyl)amino]-2-oxoethyl]imino]
Preparation of bisacetic acid: - in 80 ml of dry pyridine (dried over molecular sieves)
Heat a slurry of 9.56 g of nitrilotriacetic acid to 55°C. Add acetic anhydride (7.66g) and bring the solution to 100%
Heat to ℃. After heating for 0.5 hour, the solution is cooled to 55°C and 9.30 g of 4-bromo-3-methylaniline is added with a 5 ml pyridine rinse. solution 100
Heat at °C for 1.0 h. The reaction system is cooled and evaporated on a rotary evaporator to a paste solid, which is dissolved in 120 ml of aqueous ammonium hydroxide solution (30 ml of concentrated ammonium hydroxide/90 ml of distilled water). The clear brown solution is extracted with two 100 ml portions of methylene chloride and neutralized to PH 3 with 35 ml of concentrated HCl. Take the white solid, wash it three times with 25 ml portions of cold distilled water, and wash it under reduced pressure for 60 minutes.
Dry for 2.75 hours at °C. Crude product (12.9g)
Recrystallized from 360ml of 50% ethanol, 9.85g
A product (melting point 206.5-209.0°C) is obtained. Example 5 2,2'-[[2-[(3-bromo-4-methylphenyl)amino]-2-oxoethyl]imino]
Preparation of bisacetic acid: - in dry pyridine (dried over molecular sieves) in 40 ml.
Prepare a slurry of 4.78 g of nitrilotriacetic acid,
Heat to 50℃. Slowly add acetic anhydride (2.55 g) and heat the solution to 100°C. After heating for 0.5 h, the solution was cooled to 42°C and dissolved in 5 ml of pyridine.
Slowly add 4.81 g of 3-bromo-4-methylaniline. Heat the solution to 100 °C. After heating for 2.0 hours, the reaction system is cooled and evaporated on a rotary evaporator. This material is dissolved in 75 ml of 10% sodium hydroxide and extracted with two 50 ml portions of methylene chloride. Dilute the aqueous part with 100 ml of distilled water and add concentrated HCl.
Neutralize to PH3.2 and cool overnight for about 16 hours. Filter the reaction system and wash with cold distilled water. After drying for 3 hours at 60 °C under reduced pressure, 7.14 g of crude product is obtained (melting point 206.0~
208.0℃). Recrystallize from 150 ml of 75% ethanol to obtain 6.4 g of solid (melting point 209.0-210.0°C). Example 6 Preparation of a formulation complexed with technetium-99m:
- The table below shows exemplary formulations of the compound of formula [] and the stannous fluoride reducing agent. ligand
0.46M - Dissolved in sodium hydroxide to a final pH of approximately 6.
Prepare various formulations by obtaining solutions of ~7.5. To this is added 70% of stannous fluoride in 6M hydrochloric acid.
Add 0.01 ml of the mg/ml solution and make up the volume to ml with water for injection. The formulations in the table shown below are: Ligand: Tin=
It has a preferred molar ratio of 150:1.
【表】
オキソエチル〓イミノ〓ビス
酢酸
次に本発明化合物［］と従来の公知化合物の
肝胆管活性についての比較実験を例示する。な
お、本実験で用いた化合物は、以下の通りであ
る。
本発明化合物［］[Table] Oxoethyl imino bisacetic acid Next, a comparative experiment regarding the hepatobiliary duct activity of the compound of the present invention [ ] and a conventional known compound will be illustrated. The compounds used in this experiment are as follows. Compound of the present invention []
【式】
２，2′−［［２−［（４−ブロモ−３−メチルフエ
ニル）アミノ］−２−オキソエチル］イミノ］ビ
ス酢酸（以下、３−メチル−４−ブロモ−HIDA
と称す）[Formula] 2,2'-[[2-[(4-bromo-3-methylphenyl)amino]-2-oxoethyl]imino]bisacetic acid (hereinafter referred to as 3-methyl-4-bromo-HIDA
)
【式】
２，2′−［［２−［（３−ブロモ−２，４，６−ト
リメチルフエニル）アミノ］−２−オキソエチル］
イミノ］ビス酢酸（以下、２，４，６−トリメチ
ル−６−ブロモ−HIDAと称す）[Formula] 2,2'-[[2-[(3-bromo-2,4,6-trimethylphenyl)amino]-2-oxoethyl]
imino]bisacetic acid (hereinafter referred to as 2,4,6-trimethyl-6-bromo-HIDA)
【式】
２，2′−［［２−［（４−ブロモ−２，３，６−ト
リメチルフエニル）アミノ］−２−オキソエチル］
イミノ］ビス酢酸（以下、２，３，６−トリメチ
ル−４−ブロモ−HIDAと称す）
従来公知化合物[Formula] 2,2'-[[2-[(4-bromo-2,3,6-trimethylphenyl)amino]-2-oxoethyl]
imino]bisacetic acid (hereinafter referred to as 2,3,6-trimethyl-4-bromo-HIDA) Conventionally known compound
【式】
２，2′−［［２−［（２，６−ジメチルフエニル）
アミノ］−２−オキソエチル］イミノ］ビス酢酸
（以下、ジメチル−HIDAと称す）[Formula] 2,2'-[[2-[(2,6-dimethylphenyl)
Amino]-2-oxoethyl]imino]bisacetic acid (hereinafter referred to as dimethyl-HIDA)
【式】
２，2′−［［２−［（２，６−ジエチルフエニル）
アミノ］−２−オキソエチル］イミノ］ビス酢酸
（以下、ジエチル−HIDAと称す）[Formula] 2,2'-[[2-[(2,6-diethylphenyl)
Amino]-2-oxoethyl]imino]bisacetic acid (hereinafter referred to as diethyl-HIDA)
【式】
２，2′−［［２−［（２，６−ジイソプロピルフエ
ニル］アミノ］−２−オキソエチル］イミノ］ビ
ス酢酸（以下、ジイソプロピル−HIDAと称す）[Formula] 2,2'-[[2-[(2,6-diisopropylphenyl]amino]-2-oxoethyl]imino]bisacetic acid (hereinafter referred to as diisopropyl-HIDA)
【式】
２，2′−［［２−［（２，４，６−トリメチルフエ
ニル）アミノ］−２−オキソエチル］イミノ］ビ
ス酢酸（以下、２，４，６−トリメチル−HIDA
と称す）[Formula] 2,2'-[[2-[(2,4,6-trimethylphenyl)amino]-2-oxoethyl]imino]bisacetic acid (hereinafter referred to as 2,4,6-trimethyl-HIDA
)
【式】
２，2′−［［２−［（２，４，５−トリメチルフエ
ニル）アミノ］−２−オキソエチル］イミノ］ビ
ス酢酸（以下、２，４，５−トリメチル−HIDA
と称す）[Formula] 2,2'-[[2-[(2,4,5-trimethylphenyl)amino]-2-oxoethyl]imino]bisacetic acid (hereinafter referred to as 2,4,5-trimethyl-HIDA
)
【式】
２，2′−［［２−［（４−ヨードフエニル）アミ
ノ］−２−オキソエチル］イミノ］ビス酢酸（以
下、４−ヨード−HIDAと称す）[Formula] 2,2'-[[2-[(4-iodophenyl)amino]-2-oxoethyl]imino]bisacetic acid (hereinafter referred to as 4-iodo-HIDA)
【式】
２，2′−［［２−［（４−ヨード−２，６−ジメチ
ルフエニル）アミノ］−２−オキソエチル］イミ
ノ］ビス酢酸（以下、２，６−ジメチル−４−ヨ
ード−HIDAと称す）
但し、上記式において、Ｒは
である。
比較実験
(1) ラビツトの動態−ガンマカメラによる実験雄
ラビツト（４Kg±10％）を用いて、映像形成を
行つた。ラビツトには食物と水を任意に与え、
各ラビツトに特別にデザインしたジヤケツトに
拘束し、その間映像を観察した。麻酔剤あるい
は鎮静剤は全く使用せず、耳をアイスパツクに
15秒間適用して麻痺させた後、耳縁の静脈に、
適当なテクネチウム−99m錯体／0.9％NaClの
4mCi／ml溶液（0.25ml）を注射した。ラビツ
トのガンマカメラに面する所定位置に注射し、
腹部側からラビツトを映像形成した。
使用したガンマカメラは、MDSコンピユー
タに接続したサール（Searle）HP phoガンマ
である。140Kevピークのテクネチウム−
99mのまわりの中心に25％窓（window）があ
る。試料をラビツトの静脈に注射すると同時
に、コンピユーターの管理下でカメラを始動さ
せた。最高30分間にわたり30秒間隔で、データ
を絶えず記録した。すべての情報が得られた
後、関係領域（regions of interest）（ROI）
を映像化した。これらのROIを心臓、肝臓およ
び胆のうおよび場合によつては膀胱、賢臓およ
び腸にわたつて描いた。それが後の血液分析で
得られるものと同一形状の曲線を与えることを
確認した後、心臓のROIを血液の時間／活性曲
線を得るために用いた。
各種ROIの時間／活性曲線を用いて、異なる
錯体の比較パラメータを得た。これらのパラメ
ータは、肝臓の最大活性に対する時間
（Tnax）、およびTnaxと肝臓の活性がそのTnax
値の50％に低下する時間（T50）との時間的間
隔である。
(2) ラツトの肝胆管特異性
各テクネチウム−99m／HIDA誘導体の肝胆
管特異性を、少なくとも６匹の雄スプラーグ−
ダウレイ（Sprague−Dawley）ラツト（体重
200〜375ｇ）のグループで評価した。テクネチ
ウム−99m／HIDA誘導体錯体溶液を作成する
が、この場合、注射容量に約1mCi／mlのテク
ネチウム−99mおよび約１mg／mlのリガンドが
含まれるようにする。
ラツトは使用前24時間絶食させ、エーテルの
麻酔下で陰茎結紮を行つた後、各ラツトの外部
頚静脈に0.25ml用量を注射した。注射30分後に
殺し、対側性頚静脈から採血（1.0ml）し、肝
臓、大腸および小腸、賢臓、胃および膀胱（内
容物とともに）を取り出した。注射後30分の段
ソ時間は、肝***が平衡に達したことが示され
る時間での活性の分布を考慮して選択した。こ
れらの組識の放射能の注射量の割合は、自動式
ガンマ計数装置を用い、標準との直接比較から
決定した。
結 果
本発明化合物と従来公知化合物の比較結果を、次
表に示す。[Formula] 2,2'-[[2-[(4-iodo-2,6-dimethylphenyl)amino]-2-oxoethyl]imino]bisacetic acid (hereinafter referred to as 2,6-dimethyl-4-iodo- (referred to as HIDA) However, in the above formula, R is It is. Comparative experiment (1) Rabbit dynamics - experiment using a gamma camera Images were formed using a male rabbit (4 kg ± 10%). Rabbits were given food and water ad libitum.
Each rabbit was restrained in a specially designed jacket while viewing images. No anesthetics or sedatives are used, and the ear is covered with ice packs.
Apply for 15 seconds to numb, then apply to the vein at the edge of the ear,
Appropriate technetium-99m complex/0.9% NaCl
A 4 mCi/ml solution (0.25 ml) was injected. Inject it at the designated location facing Rabbit's gamma camera,
The rabbit was imaged from the ventral side. The gamma camera used was a Searle HP pho gamma connected to an MDS computer. Technetium at 140Kev peak
There is a 25% window in the center around 99m. At the same time as the sample was injected into the rabbit's vein, the camera was started under computer control. Data was recorded continuously at 30 second intervals for up to 30 minutes. After all information is obtained, regions of interest (ROI)
was visualized. These ROIs were drawn across the heart, liver and gallbladder and in some cases the bladder, viscera and intestines. The heart ROI was used to obtain the blood time/activity curve after confirming that it gave a curve of the same shape as that obtained in the subsequent blood analysis. The time/activity curves of various ROIs were used to obtain comparative parameters of different complexes. These parameters are the time to maximal activity of the liver (T nax ), and the time to maximal activity of the liver (T nax ), and the time to maximal activity of the liver
It is the time interval from which the value decreases to 50% of its value (T 50 ). (2) Hepatobiliary specificity in rats The hepatobiliary specificity of each technetium-99m/HIDA derivative was determined in at least six male Sprague rats.
Sprague-Dawley rat (weight
(200-375g) group. A technetium-99m/HIDA derivative complex solution is prepared such that the injection volume contains about 1 mCi/ml technetium-99m and about 1 mg/ml ligand. Rats were fasted for 24 hours before use, and a 0.25 ml dose was injected into the external jugular vein of each rat after penile ligation under ether anesthesia. Thirty minutes after injection, the animals were sacrificed, blood was collected (1.0 ml) from the contralateral jugular vein, and the liver, large and small intestines, viscera, stomach, and bladder (along with their contents) were removed. The step time of 30 minutes after injection was chosen considering the distribution of activity at the time when hepatic excretion was shown to have reached equilibrium. The proportion of radioactivity injected in these tissues was determined from direct comparison with standards using an automated gamma counter. Results Comparison results between the compounds of the present invention and conventionally known compounds are shown in the following table.
【表】
結 論
肝胆管系の良好な映像形成剤は、短い腎性抽出
（extraction）時間、長い肝抽出時間および短い
肝胆管移行時間を有しなければならない。これら
の条件は、本発明化合物によつて十分満足される
が、従来公知化合物では満足されないことが認め
られる。すなわち、本発明化合物は、従来公知化
合物と比較して、肝胆管映像形成剤として優れて
いることが明らかである。[Table] Conclusion A good imaging agent for the hepatobiliary system should have a short renal extraction time, a long hepatic extraction time and a short hepatobiliary transit time. It is recognized that these conditions are fully satisfied by the compounds of the present invention, but not by conventionally known compounds. That is, it is clear that the compound of the present invention is superior as a hepatobiliary duct imaging agent compared to conventionally known compounds.
Claims (1)
メチルまたはエチル、 R2とR3の一方は炭素数１〜４のアルキルで、
他方は臭素またはヨウ素、および ｎは０である］ を有する化合物またはその医薬的に許容しうる水
溶性塩。 ２ R1とR4が共にメチルである前記第１項記載
の化合物。 ３ R2とR3の一方がメチルまたはエチルである
前記第１項または第２項記載の化合物またはその
医薬的に許容しうる水溶性塩。 ４ ２，2′−［［２−［（３−ブロモ−２，４，６−
トリメチルフエニル）アミノ］−２−オキソエチ
ル］イミノ］ビス酢酸である前記第１項記載の化
合物。 ５ ２，2′−［［２−［（３−ブロモ−２，６−ジエ
チル−４−メチルフエニル）アミノ］−２−オキ
ソエチル］イミノ］ビス酢酸である前記第１項記
載の化合物。 ６ ２，2′−［［２−［（３−ヨ−ド−４−メチルフ
エニル）アミノ］−２−オキソエチル］イミノ］
ビス酢酸である前記第１項記載の化合物。 ７ ２，2′−［［２−［（４−ブロモ−３−メチルフ
エニル）アミノ］−２−オキソエチル］イミノ］
ビス酢酸である前記第１項記載の化合物。 ８ ２，2′−［［２−［（３−ブロモ−４−メチルフ
エニル）アミノ］−２−オキソエチル］イミノ］
ビス酢酸である前記第１項記載の化合物。[Claims] 1 formula, [In the formula, R 1 and R 4 are each independently hydrogen,
Methyl or ethyl, one of R 2 and R 3 is alkyl having 1 to 4 carbon atoms,
the other is bromine or iodine, and n is 0] or a pharmaceutically acceptable water-soluble salt thereof. 2. The compound according to item 1 above, wherein R 1 and R 4 are both methyl. 3. The compound according to item 1 or 2 above, or a pharmaceutically acceptable water-soluble salt thereof, wherein one of R 2 and R 3 is methyl or ethyl. 4 2,2'-[[2-[(3-bromo-2,4,6-
The compound according to item 1 above, which is trimethylphenyl)amino]-2-oxoethyl]imino]bisacetic acid. 5. The compound according to item 1 above, which is 2,2'-[[2-[(3-bromo-2,6-diethyl-4-methylphenyl)amino]-2-oxoethyl]imino]bisacetic acid. 6 2,2'-[[2-[(3-iodo-4-methylphenyl)amino]-2-oxoethyl]imino]
The compound according to item 1 above, which is bisacetic acid. 7 2,2'-[[2-[(4-bromo-3-methylphenyl)amino]-2-oxoethyl]imino]
The compound according to item 1 above, which is bisacetic acid. 8 2,2'-[[2-[(3-bromo-4-methylphenyl)amino]-2-oxoethyl]imino]
The compound according to item 1 above, which is bisacetic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22115580A | 1980-12-29 | 1980-12-29 | |
| US221155 | 1980-12-29 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1256895A Division JPH02160727A (en) | 1980-12-29 | 1989-09-28 | Composition for forming external image of |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58948A JPS58948A (en) | 1983-01-06 |
| JPH0237345B2 true JPH0237345B2 (en) | 1990-08-23 |
Family
ID=22826582
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56216075A Granted JPS58948A (en) | 1980-12-29 | 1981-12-23 | N-substituted diacetic acids |
| JP1256895A Granted JPH02160727A (en) | 1980-12-29 | 1989-09-28 | Composition for forming external image of |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1256895A Granted JPH02160727A (en) | 1980-12-29 | 1989-09-28 | Composition for forming external image of |
Country Status (15)
| Country | Link |
|---|---|
| JP (2) | JPS58948A (en) |
| AT (1) | AT377975B (en) |
| AU (1) | AU539726B2 (en) |
| BE (1) | BE891534A (en) |
| CA (1) | CA1187897A (en) |
| CH (1) | CH649761A5 (en) |
| DE (1) | DE3151686A1 (en) |
| FR (1) | FR2497197B1 (en) |
| GB (1) | GB2090252B (en) |
| IE (1) | IE52900B1 (en) |
| IT (1) | IT1140400B (en) |
| LU (1) | LU83856A1 (en) |
| NL (1) | NL193318C (en) |
| SE (2) | SE461015B (en) |
| ZA (1) | ZA818943B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4454107A (en) * | 1982-08-30 | 1984-06-12 | Merck & Co., Inc. | Tc99m-Phenida, radioscintigraphic agent for diagnosis of hepatoniliary disease |
| GB8413772D0 (en) * | 1984-05-30 | 1984-07-04 | Nyegaard & Co As | Chemical compounds |
| JPH0331486Y2 (en) * | 1985-06-24 | 1991-07-04 | ||
| JPH01143751A (en) * | 1987-11-18 | 1989-06-06 | Corns & Co Ltd | Low-pressure casting device and casting method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4017596A (en) * | 1975-03-03 | 1977-04-12 | Research Corporation | Radiopharmaceutical chelates and method of external imaging |
| JPS5587726A (en) * | 1978-12-21 | 1980-07-02 | Hoechst Ag | Lever function diagnostic agent |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3725295A (en) * | 1971-07-20 | 1973-04-03 | Atomic Energy Commission | Technetium labeling |
| CA1070695A (en) * | 1975-09-02 | 1980-01-29 | Michael D. Loberg | Iminodiacetic acid pharmaceutical |
| CH607920A5 (en) * | 1976-05-31 | 1978-12-15 | Solco Basel Ag | |
| PL115524B1 (en) * | 1978-04-10 | 1981-04-30 | Uniwersytet Warszawski | Process for manufacturing scintigraphic agent |
| DE2920174A1 (en) * | 1979-05-18 | 1980-11-20 | Hoechst Ag | TECHNETIUM-99M-MARKED ACETANILIDOIMINODIACETATE FOR LIVER FUNCTION DIAGNOSTICS |
-
1981
- 1981-12-10 CA CA000392015A patent/CA1187897A/en not_active Expired
- 1981-12-17 GB GB8138054A patent/GB2090252B/en not_active Expired
- 1981-12-18 IE IE3110/81A patent/IE52900B1/en not_active IP Right Cessation
- 1981-12-18 BE BE0/206879A patent/BE891534A/en not_active IP Right Cessation
- 1981-12-21 FR FR8123803A patent/FR2497197B1/en not_active Expired
- 1981-12-22 CH CH8210/81A patent/CH649761A5/en not_active IP Right Cessation
- 1981-12-23 JP JP56216075A patent/JPS58948A/en active Granted
- 1981-12-23 AU AU78808/81A patent/AU539726B2/en not_active Expired
- 1981-12-24 NL NL8105845A patent/NL193318C/en not_active IP Right Cessation
- 1981-12-24 LU LU83856A patent/LU83856A1/en unknown
- 1981-12-28 ZA ZA818943A patent/ZA818943B/en unknown
- 1981-12-28 SE SE8107806A patent/SE461015B/en not_active IP Right Cessation
- 1981-12-28 DE DE19813151686 patent/DE3151686A1/en active Granted
- 1981-12-28 IT IT25861/81A patent/IT1140400B/en active
- 1981-12-29 AT AT0561381A patent/AT377975B/en active
-
1987
- 1987-09-18 SE SE8703623A patent/SE466788B/en not_active IP Right Cessation
-
1989
- 1989-09-28 JP JP1256895A patent/JPH02160727A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4017596A (en) * | 1975-03-03 | 1977-04-12 | Research Corporation | Radiopharmaceutical chelates and method of external imaging |
| JPS5587726A (en) * | 1978-12-21 | 1980-07-02 | Hoechst Ag | Lever function diagnostic agent |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2090252A (en) | 1982-07-07 |
| SE8703623L (en) | 1987-09-18 |
| SE466788B (en) | 1992-04-06 |
| AU539726B2 (en) | 1984-10-11 |
| IE52900B1 (en) | 1988-04-13 |
| CA1187897A (en) | 1985-05-28 |
| DE3151686A1 (en) | 1982-07-08 |
| FR2497197B1 (en) | 1986-04-11 |
| SE461015B (en) | 1989-12-18 |
| FR2497197A1 (en) | 1982-07-02 |
| IE813110L (en) | 1982-06-29 |
| CH649761A5 (en) | 1985-06-14 |
| ZA818943B (en) | 1982-11-24 |
| JPS58948A (en) | 1983-01-06 |
| SE8107806L (en) | 1982-06-30 |
| LU83856A1 (en) | 1982-07-07 |
| SE8703623D0 (en) | 1987-09-18 |
| AT377975B (en) | 1985-05-28 |
| BE891534A (en) | 1982-04-16 |
| GB2090252B (en) | 1985-01-03 |
| NL8105845A (en) | 1982-07-16 |
| NL193318B (en) | 1999-02-01 |
| ATA561381A (en) | 1984-10-15 |
| IT1140400B (en) | 1986-09-24 |
| JPH02160727A (en) | 1990-06-20 |
| AU7880881A (en) | 1982-07-08 |
| JPH0316327B2 (en) | 1991-03-05 |
| NL193318C (en) | 1999-06-02 |
| IT8125861A0 (en) | 1981-12-28 |
| DE3151686C2 (en) | 1990-12-20 |
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