WO1990002571A1 - Radiopharmaceutical products consisting of tetraphosphonate complexes - Google Patents
Radiopharmaceutical products consisting of tetraphosphonate complexes Download PDFInfo
- Publication number
- WO1990002571A1 WO1990002571A1 PCT/FR1989/000473 FR8900473W WO9002571A1 WO 1990002571 A1 WO1990002571 A1 WO 1990002571A1 FR 8900473 W FR8900473 W FR 8900473W WO 9002571 A1 WO9002571 A1 WO 9002571A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- radicals
- pharmaceutically acceptable
- composition according
- tetraphosphonate
- Prior art date
Links
- 239000012217 radiopharmaceutical Substances 0.000 title claims abstract description 18
- 229940121896 radiopharmaceutical Drugs 0.000 title claims abstract description 9
- 230000002799 radiopharmaceutical effect Effects 0.000 title claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 24
- 229910052713 technetium Inorganic materials 0.000 claims abstract description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- 229910052702 rhenium Inorganic materials 0.000 claims abstract description 10
- 229910052727 yttrium Inorganic materials 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 40
- 239000002253 acid Substances 0.000 claims description 24
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 17
- 239000003638 chemical reducing agent Substances 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 150000003254 radicals Chemical class 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- -1 cyclic radical Chemical class 0.000 claims description 11
- 239000003381 stabilizer Substances 0.000 claims description 11
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims description 11
- 150000007513 acids Chemical class 0.000 claims description 8
- 235000010323 ascorbic acid Nutrition 0.000 claims description 8
- 229960005070 ascorbic acid Drugs 0.000 claims description 8
- 239000011668 ascorbic acid Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 claims description 6
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 4
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 150000005840 aryl radicals Chemical class 0.000 claims description 4
- 229910052718 tin Inorganic materials 0.000 claims description 4
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical group Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 4
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical group [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 238000003745 diagnosis Methods 0.000 claims description 3
- 230000002285 radioactive effect Effects 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- WUAPFZMCVAUBPE-NJFSPNSNSA-N 188Re Chemical compound [188Re] WUAPFZMCVAUBPE-NJFSPNSNSA-N 0.000 claims description 2
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-araboascorbic acid Natural products OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 claims description 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 2
- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 claims description 2
- UZEDIBTVIIJELN-UHFFFAOYSA-N chromium(2+) Chemical class [Cr+2] UZEDIBTVIIJELN-UHFFFAOYSA-N 0.000 claims description 2
- 235000010350 erythorbic acid Nutrition 0.000 claims description 2
- 239000004318 erythorbic acid Substances 0.000 claims description 2
- 229960005219 gentisic acid Drugs 0.000 claims description 2
- 229940026239 isoascorbic acid Drugs 0.000 claims description 2
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 claims description 2
- 229940056501 technetium 99m Drugs 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 abstract description 11
- 239000000243 solution Substances 0.000 description 26
- 239000000047 product Substances 0.000 description 25
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000007469 bone scintigraphy Methods 0.000 description 13
- 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 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229910052708 sodium Inorganic materials 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 101000795744 Homo sapiens TPA-induced transmembrane protein Proteins 0.000 description 8
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 8
- 102100031626 TPA-induced transmembrane protein Human genes 0.000 description 8
- HJZKOAYDRQLPME-UHFFFAOYSA-N oxidronic acid Chemical compound OP(=O)(O)C(O)P(O)(O)=O HJZKOAYDRQLPME-UHFFFAOYSA-N 0.000 description 8
- 229960004230 oxidronic acid Drugs 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 239000011135 tin Substances 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000003642 osteotropic effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 150000003495 technetium Chemical class 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 2
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- MDAXKAUIABOHTD-UHFFFAOYSA-N 1,4,8,11-tetraazacyclotetradecane Chemical compound C1CNCCNCCCNCCNC1 MDAXKAUIABOHTD-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- JKTORXLUQLQJCM-UHFFFAOYSA-N 4-phosphonobutylphosphonic acid Chemical compound OP(O)(=O)CCCCP(O)(O)=O JKTORXLUQLQJCM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- HWZUDASOMGNLSM-UHFFFAOYSA-N O=P1OCOP(=O)O1 Chemical compound O=P1OCOP(=O)O1 HWZUDASOMGNLSM-UHFFFAOYSA-N 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- KATXJJSCAPBIOB-UHFFFAOYSA-N cyclotetradecane Chemical compound C1CCCCCCCCCCCCC1 KATXJJSCAPBIOB-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical group [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000007580 dry-mixing Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940102859 methylene diphosphonate Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- OLAPPGSPBNVTRF-UHFFFAOYSA-N naphthalene-1,4,5,8-tetracarboxylic acid Chemical compound C1=CC(C(O)=O)=C2C(C(=O)O)=CC=C(C(O)=O)C2=C1C(O)=O OLAPPGSPBNVTRF-UHFFFAOYSA-N 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010405 reoxidation reaction Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019832 sodium triphosphate Nutrition 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000005287 template synthesis Methods 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- YJBKVPRVZAQTPY-UHFFFAOYSA-J tetrachlorostannane;dihydrate Chemical compound O.O.Cl[Sn](Cl)(Cl)Cl YJBKVPRVZAQTPY-UHFFFAOYSA-J 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
-
- 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
- A61K51/0482—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 chelates from cyclic ligands, e.g. DOTA
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Definitions
- the present invention relates to radiopharmaceuticals having in particular a bone tropism, which consist of complexes of Te, Y or Re usable for diagnosis or therapy, for example osteotropic complexes of technetium (99 mTc) for bone scintigraphy.
- a bone tropism which consist of complexes of Te, Y or Re usable for diagnosis or therapy, for example osteotropic complexes of technetium (99 mTc) for bone scintigraphy.
- the ligands used up to now to form technetium complexes belong to the class of polyphosphates and diphosphonates.
- osteotropic vectors belonging especially to the class of diphosphonates.
- These vectors are for example methylene diphosphonate (HDP) described in American patent US-A-4032625, hydroxymethylene diphosphonate (HMDP) described in the second "International Symposium on Radiopharmaceuti cals", March 19-22, 1979, Seattle, Washington , p.645-654, and propane diphosphonate-1,1 dicarboxylate-2,3 (DPD) described in the German patent DE-A-2755874.
- HDP methylene diphosphonate
- HMDP hydroxymethylene diphosphonate
- DPD propane diphosphonate-1,1 dicarboxylate-2,3
- diphosphonates such as MDP, HMDP and DPD give satisfactory results, it would be interesting to further improve the performance of the ligands used in order to be able to carry out the examination even faster, while obtaining good contrast between the bones. and soft tissue, without having hepatic uptake.
- the present invention specifically relates to new radiopharmaceutical products constituted by Tc, Re or Y complexes which make it possible to obtain improved results, in particular for the preparation of technetium-based agents for bone scintigraphy.
- this new radiopharmaceutical product consists of a technetium, rhenium or yttrium complex comprising a tetraphosphonate ligand chosen from tetraphosphonic acids corresponding to the formula: (I) in which is a cyclic radical corresponding to the formulas:
- n which may be identical or different, are integers ranging from 2 to 4, and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , which may be identical or different, represent a hydrogen atom or a radical chosen from alkyl radicals, the radicals of formula
- R 7 and R 8 which are identical or different represent a hydrogen atom or an alkyl or aryl radical
- the radicals of formula (CH 2 ) n -COOR 9 in which n is an integer from 1 to 5 and R 9 represents a hydrogen atom, NH 4 , a physiologically acceptable metal M 1 / v with v representing the valence of the metal M or an alkyl radical, the radicals of formula:
- n, R 7 and R 8 have the meaning given above and the radicals of formula SO 3 R 9 in which R 9 has the meaning given above, and the pharmaceutically acceptable salts and esters of these tetraphosphonic acids.
- the alkyl radicals used as substituents generally have from 1 to 10, preferably 1 to 5 carbon atoms and can be linear or branched.
- the aryl radicals used can be linked to the heteroatomic or homoatomic cycle by 1 to 5 carbon atoms. They can be constituted by the simple or substituted phenyl radical.
- substituents used are derived from an amine, a carboxylic acid or an ester, they can be linked to the hetero atomic or homoatomic cycle by one or more CH 2 groups, generally by 1 CH 2 group.
- substituents of the ring are halogen atoms, they may be fluorine, chlorine, bromine or iodine atoms.
- n are equal to 2 or 3.
- tetraphosphonate ligands can be prepared by various methods.
- the tetraaza compound of formula (VII) which serves as starting material for this synthesis can be obtained by conventional methods, for example by condensation reaction assisted by a transition metal (template synthesis).
- the product is also available commercially.
- This synthesis corresponds to the Arbusov reaction followed by an acid hydrolysis of the tetraphosphonate obtained.
- the compound of formula (IX) used as starting material for this synthesis can be obtained by conventional methods, for example by the action of bromine on 1,2,4,5, tetra methyl Ibenzene. This product is commercially available.
- the choice of the isotopes of Te, Y or Re used depends in particular on the use of the product.
- yttrium 90 or rhenium 186 or 188 which have longer periods and emit more effective radiation for therapeutic treatments.
- the subject of the invention is also a composition for the preparation of a radiopharmaceutical product comprising a radioactive isotope such as technetium, which comprises:
- the composition also comprises at least one reducing agent which is intended to reduce technetium or rhenium during the preparation of the complex.
- the pharmaceutically acceptable salts of tetraphosphonic acids which can be used in the invention can be, for example, alkali metal, alkaline earth metal, heavy metal or ammonium salts.
- Alkaline salts such as sodium, potassium or lithium salts as well as ammonium salts are generally preferred.
- esters of the tetraphosphonic acids of the invention can be lower alkyl esters, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutylic and pentylic esters.
- composition of the invention it is possible to use salts or esters which correspond to the replacement of all the hydrogen atoms of the PO 3 H 2 groups or of only part of these hydrogen atoms.
- mixtures of salts for example a mixture of sodium and potassium salts.
- the tin, iron or chromium salts which can be used as reducing agent can be in particular chlorides and sulfates.
- tin (II) chloride is used.
- They can be present in the form of hydrated salts, such as tin chloride dihydrate.
- composition of the invention a stabilizing agent, the composition against oxidation and / or hydrolysis.
- This agent is to prevent the oxidation of the reducing agent during the storage of the composition and to prevent, for example, the reoxidation of technetium or reduced rhenium after formation of the compound.
- the stabilizing agent can be chosen in particular from ascorbic acid, gentisic acid, erythorbic acid, their salts and esters. pharmaceutically acceptable, and mixtures thereof.
- the contents of tetraphosphonate ligand, of reducing agent and of stabilizing agent can vary within a wide range.
- the molar ratio of the reducing agent to the ligand can vary from 1/1 to 1/150. Generally this molar ratio is in the range of 1/1 to 1/10, preferably from 1 / 1.5 to 1 / 4.5.
- the amount of stabilizing agent used is generally small and preferably does not exceed 25% by weight.
- compositions of the invention can comprise:
- compositions of the invention are intended for intravenous injection into living beings and therefore suitable conditions must be used. manufacturing and processing to obtain suitably sterile and pyrogen-free compositions.
- compositions can be prepared by simple dry mixing of the reducing agent, the tetraphosphonate ligand and the stabilizer.
- compositions of the invention can also be prepared in the form of an aqueous solution in sterile, pyrogen-free water.
- the ligand is dissipated and, if necessary, the reducing age and the stabilizer (s) in an aqueous solution using deoxygenated water.
- This composition can be introduced into a bottle and stored under nitrogen when it contains an agent reducing agent to minimize untimely oxidation of the reducing agent during storage.
- the compositions of the invention are prepared in lyophilized form.
- the composition is lyophilized using conventional equipment.
- sterile deoxygenated water is used for the manufacture and the product is stored under nitrogen.
- pH is adjusted to an appropriate value, generally situated in the range from 5 to 7, preferably to around 6, for example by addition of soda or hydrochloric acid.
- the composition is dissolved using an isotonic solution of the isotope used, for example pertechnetate-99 m of alkali metal or ammonium from a commercial source of technetium to obtain a radiopharmaceuti that for bone scintigraphy suitable for intravenous injection.
- an isotonic solution of the isotope used for example pertechnetate-99 m of alkali metal or ammonium from a commercial source of technetium to obtain a radiopharmaceuti that for bone scintigraphy suitable for intravenous injection.
- the injection can be carried out from 15 minutes after the addition of the isotope solution.
- an alkali metal or ammonium perrhenate solution can be used, which will expediently be reduced to an oxidation state of less than +7.
- an alkali metal or ammonium perrhenate solution can be used, which will expediently be reduced to an oxidation state of less than +7.
- the isotope is yttrium
- a solution of nitrate, chloride or other yttrium III salt can be used.
- the amounts of tetraphosphonate ligands can range from 0.1 to 10 milligrams per examination depending on the tetraphosphonate ligand used and its toxicity.
- the amount of associated reducing agent can be from 0.01 to 2.5 milligrams.
- tetraphosphonate ligands ranging from 0.1 to 5 milligrams for an adult weighing 50 to 100 kilograms.
- the total dose of technetium for a precise examination of the skeleton is generally between 370 and 740 Mbq (10 to 20 millicuries).
- This tet raphosphonic acid is prepared by the MANNICH reaction which corresponds to the following reaction scheme:
- the acid 2 is recovered by filtration, washed with water and recrystallized from water (the dissolution is carried out at reflux by addition of NaOH and the pH is brought back to 1.5 by HCl before precipitation).
- a white crystallized solid is thus obtained, having a melting point above 250 ° C and the following structure:
- a mixture of 0.022 mole (10g) of tetrakisbromomethyl-1,2,4,5 benzene and 0.096 mole is brought to reflux for 6 hours at 120 ° C. in a three-necked flask equipped with a condenser and a thermometer. (20 g) triisopropyl phosphite.
- a white crystalline solid is thus obtained, having a melting point above 250 ° C corresponding to formula (V).
- This compound contains an amount of sodium varying between 2 and 5%.
- the molecular mass which corresponds to the free acid C 10 H 18 O 12 P 4 is 454.12.
- TTMP expressed in mass of free phosphonic acid, after determination of the water and of the sodium optionally present, obtained in Example 1, are dissolved in 2 ml of 0.9% sodium chloride solution and the pH of the solution at about 7 with 0.1 N sodium hydroxide solution
- tin (II) chloride dihydrate dissolved in 0.01 N hydrochloric acid solution (7.5 mg / ml solution) is added, and 1.25 mg of ascorbic acid from '' an aqueous solution at 12.5 mg / ml.
- the pH is brought to values between pH5 and 7 by addition of base or acid.
- the bottle is capped and purged for 15 minutes by flushing with nitrogen.
- the solutions are then distributed in bottles under nitrogen by introducing into each bottle 1 ml of solution for each pH and the product is lyophilized in the bottles.
- Example 3 The same procedure is followed as in Example 3 to prepare this composition using 5 mg of BTMP (expressed in mass of free phosphonic acid after determination of the water and of the sodium which may be present) instead of 5 mg of TTMP . Chromatographic analysis carried out under the same conditions as those of Example 3 shows that the amount of free pertechnetate is less than 5% and that this value remains stable for at least 6 hours.
- a sodium pertechnetate solution 99 mTC
- 2 ⁇ Curie at 100 mCurie 74 kBq to 3.7 GBq
- the bottle is shaken to dissolve the lyophilisate and the pertechnetate reduction reaction takes place in 15 minutes.
- the solution obtained remains stable for at least 6 hours.
- Example 7 the properties of the composition obtained in Example 7 are tested from the lyophilized bottles having, before lyophilization, a pH of 6 for scintigraphy.
- Example 7 rats weighing on average 200 ⁇ 20 g are used and the products prepared in Example 7 are injected intravenously with 0.3 mg of tet raphosphoni acid per kg of body mass, which corresponds to 0.15 ml of the products obtained in Example 7 by adding 5 ml of sodium pertechnetate solution to the lyophilized bottle.
- the rats are then sacrificed in groups of three, 30 minutes, 60 minutes, 120 minutes or 180 minutes after the injection.
- the different organs are removed and their radioactivity is determined.
- the radioactivity of the urine is also determined as a function of time by a gamma camera acquisition experiment.
- Example 7 Male rats weighing 200 ⁇ 20 g are also used and the product prepared in Example 7 is injected into them from lyophilized flasks at pH 6 at a rate of 0.3 mg per kg.
- Example 8 the properties of the product obtained in Example 8 are tested in rats.
- Example 9 the same procedure is followed as in Example 9 to test the properties for bone scintigraphy of the product of the prior art HMDP (Sn) 99m Te by injecting the rat with 0.1 mg of HMDP per kilogram of body mass.
- HMDP was obtained from vials containing 2 mg of HMDP, 0.3 mg of tin chloride SnCl 2 , 2H 2 O and 0.5 mg of ascorbic acid, by adding 5 ml of a solution to the vials sodium pertechnetate. The results obtained are given in Table 5.
- Example 10 the same procedure is followed as in Example 10 to test the properties of HMDP (Sn) 99m Te from bottles identical to those used in Comparative Example 1, by injecting the product at a dose of 0, 1 mg per kilogram of body mass.
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Abstract
The invention concerns radiopharmaceutical products consisting of Tc, Y or Re complexes containing a tetraphosphonate ligand of general formula (I), wherein (α) is a cyclic radical of formula (II) or (III). R?1, R2, R3, R4, R5, and R6¿ are hydrogen atoms, for example. These products can be used for scintigraphy of bone.
Description
PRODUITS RADIOPHARMACEUTIQUES CONSTITUES PAR DES RADIOPHARMACEUTICAL PRODUCTS CONSTITUTED BY
COMPLEXES TETRAPHOSPHONATES TETRAPHOSPHONATE COMPLEXES
DESCRIPTION DESCRIPTION
La présente invention concerne des produits radiopharmaceutiques présentant en particulier un tropisme osseux, qui sont constitués par des complexes de Te, Y ou Re utilisables pour le diagnostic ou la thérapie, par exemple des complexes ostéotropes de technétium (99 mTc) pour la scintigraphie osseuse. The present invention relates to radiopharmaceuticals having in particular a bone tropism, which consist of complexes of Te, Y or Re usable for diagnosis or therapy, for example osteotropic complexes of technetium (99 mTc) for bone scintigraphy.
L'examen des os par scintigraphie osseuse suppose l'emploi de complexes de technétium ayant une affinité pour le squelette, et en particulier pour les sites actifs du squelette qui présentent certains troubles tels que des métastases. Examination of the bones by bone scintigraphy presupposes the use of technetium complexes having an affinity for the skeleton, and in particular for the active sites of the skeleton which exhibit certain disorders such as metastases.
Les ligands utilisés jusqu'à présent pour former les complexes de technétium appartiennent à la classe des po lyphosphates et des diphosphonates. The ligands used up to now to form technetium complexes belong to the class of polyphosphates and diphosphonates.
Ainsi en avril 1971, G. SUBRAHANIAN et J. 6. McAfee ont décrit dans Radiologie, 99, p.192-196, 1971, un agent pour la préparation de complexes de technétium pour la scintigraphi e osseuse constitué d'un mélange de tripolyphosphate et de chlorure d'étain (II). Ce produit a une bonne affinité pour l'os mais il a le désavantage de se localiser assez lentement dans le squelette et de ne permettre un bon examen que plusieurs heures après l'injection du produit. Thus in April 1971, G. SUBRAHANIAN and J. 6. McAfee described in Radiology, 99, p.192-196, 1971, an agent for the preparation of technetium complexes for bone scintigraphy consisting of a mixture of tripolyphosphate and tin (II) chloride. This product has a good affinity for the bone but it has the disadvantage of being localized rather slowly in the skeleton and of allowing a good examination only several hours after the injection of the product.
Aussi, depuis lors, des recherches ont été entreprises pour développer et tester d'autres ligands ostéotropes parmi la classe des phosphates inorganiques et des phosphonates. Ces recherches ont abouti à l'utilisation de différents vecteurs ostéotropes appartenant surtout à la classe des diphosphonates. Ces
vecteurs sont par exemple le méthylène diphosphonate (HDP) décrit dans le brevet américain US-A-4032625, l'hydroxyméthylène diphosphonate (HMDP) décrit dans le deuxième "International Symposium on Radiopharmaceuti cals", March 19-22, 1979, Seattle, Washington, p.645-654, et le propane diphosphonate-1,1 dicarboxylate-2,3 (DPD) décrit dans le brevet allemand DE-A-2755874. Ces trois di phosphonates ont en commun une structure dans laquelle Les deux groupements diphosphonate sont liés au même atome de carbone. Also, since then, research has been undertaken to develop and test other osteotropic ligands among the class of inorganic phosphates and phosphonates. This research resulted in the use of various osteotropic vectors belonging especially to the class of diphosphonates. These vectors are for example methylene diphosphonate (HDP) described in American patent US-A-4032625, hydroxymethylene diphosphonate (HMDP) described in the second "International Symposium on Radiopharmaceuti cals", March 19-22, 1979, Seattle, Washington , p.645-654, and propane diphosphonate-1,1 dicarboxylate-2,3 (DPD) described in the German patent DE-A-2755874. These three di phosphonates have in common a structure in which the two diphosphonate groups are linked to the same carbon atom.
En scintigraphie osseuse il est important que le produit utilisé permette d'obtenir une captation rapide de la radioactivité par le squelette, et une clairance rapide du sang et des tissus mous, sans donner de captation hépatique. In bone scintigraphy it is important that the product used allows rapid capture of radioactivity by the skeleton, and rapid clearance of blood and soft tissues, without giving hepatic capture.
Bien que les diphosphonates tels que le MDP, HMDP et le DPD donnent des résultats satisfaisants, il serait intéressant d'améliorer encore les performances des ligands utilisés pour pouvoir réaliser l'examen encore plus rapidement, tout en obtenant un bon contraste entre l'os et les tissus mous, sans avoir de captation hépatique. Although diphosphonates such as MDP, HMDP and DPD give satisfactory results, it would be interesting to further improve the performance of the ligands used in order to be able to carry out the examination even faster, while obtaining good contrast between the bones. and soft tissue, without having hepatic uptake.
La présente invention a précisément pour objet de nouveaux produits radiopharmaceutiques constitués par des complexes de Tc, Re ou Y qui permettent d'obtenir des résultats améliorés, notamment pour la préparation d'agents à base de technétium pour la scintigraphie osseuse. The present invention specifically relates to new radiopharmaceutical products constituted by Tc, Re or Y complexes which make it possible to obtain improved results, in particular for the preparation of technetium-based agents for bone scintigraphy.
Selon l'invention, ce nouveau produit radiopharmaceutique est constitué par un complexe de technétium, de rhénium ou d'yttrium comportant un ligand tétraphosphonate choisi parmi les acides tétraphosphoniques répondant à la formule :
( I )
dans laquelle est un radical cyclique répondant aux formules :According to the invention, this new radiopharmaceutical product consists of a technetium, rhenium or yttrium complex comprising a tetraphosphonate ligand chosen from tetraphosphonic acids corresponding to the formula: (I) in which is a cyclic radical corresponding to the formulas:
dans laquelle R7 et R8 qui sont identiques ou différents représentent un atome d'hydrogène ou un radical alkyle ou aryle, les radicaux de formule (CH2)n-COOR9 dans laquelle n est un nombre entier de 1 à 5 et R9 représente un atome d'hydrogène, NH4, un métal physiologiquement acceptable M1/v avec v représentant la valence du métal M ou un radical alkyle, les radicaux de formule :
in which R 7 and R 8 which are identical or different represent a hydrogen atom or an alkyl or aryl radical, the radicals of formula (CH 2 ) n -COOR 9 in which n is an integer from 1 to 5 and R 9 represents a hydrogen atom, NH 4 , a physiologically acceptable metal M 1 / v with v representing the valence of the metal M or an alkyl radical, the radicals of formula:
dans laquelle n, R7 et R8 ont la signification donnée ci-dessus et les radicaux de formule SO3R9 dans laquelle R9 a la signification donnée ci-dessus, et les sels et esters pharmaceutiquement acceptables de ces acides tétraphosphoniques. in which n, R 7 and R 8 have the meaning given above and the radicals of formula SO 3 R 9 in which R 9 has the meaning given above, and the pharmaceutically acceptable salts and esters of these tetraphosphonic acids.
Dans les formules données ci-dessus, les radicaux alkyle utilisés comme substituants ont généralement de 1 à 10, de préférence 1 à 5 atomes de carbone et peuvent être linéaires ou ramifiés. Les radicaux aryle utilisés peuvent être reliés au cycle hétéroatomique ou homoatomique par 1 à 5 atomes de carbone. Ils peuvent être constitués par le radical phényle simple ou substitué. In the formulas given above, the alkyl radicals used as substituents generally have from 1 to 10, preferably 1 to 5 carbon atoms and can be linear or branched. The aryl radicals used can be linked to the heteroatomic or homoatomic cycle by 1 to 5 carbon atoms. They can be constituted by the simple or substituted phenyl radical.
Lorsque les substituants utilisés sont dérivés d'une aminé, d'un acide carboxylique ou d'un ester, ils peuvent être reliés au cycle hétéro-atomique ou homoatomique par un ou plusieurs groupements CH2, généralement par 1 groupement CH2. When the substituents used are derived from an amine, a carboxylic acid or an ester, they can be linked to the hetero atomic or homoatomic cycle by one or more CH 2 groups, generally by 1 CH 2 group.
Lorsque les substituants du cycle sont des atomes d'halogène, il peut s'agir d'atomes de fluor, de chlore, de brome ou d'iode. When the substituents of the ring are halogen atoms, they may be fluorine, chlorine, bromine or iodine atoms.
De préférence m et n sont égaux à 2 ou à 3. Preferably m and n are equal to 2 or 3.
A titre d'exemples de ligands tétraphosphonates conformes à l'invention, on peut citer ceux répondant aux formules ci-dessous et leurs sels et esters pharmaceutiquement acceptables : As examples of tetraphosphonate ligands in accordance with the invention, mention may be made of those corresponding to the formulas below and their pharmaceutically acceptable salts and esters:
(IV)
(V)
(IV) (V)
Ces ligands tétraphosphonates peuvent être préparés par différents procédés. These tetraphosphonate ligands can be prepared by various methods.
Dans le cas des ligands tétraphosphonates répondant à la formule : In the case of tetraphosphonate ligands corresponding to the formula:
(VI)
dans laquelle m, n, R1, R2, R3 et R4 ont la signification donnée ci-dessus, on peut faire réagir un composé tetraaza de formule : (VI) in which m, n, R 1 , R 2 , R 3 and R 4 have the meaning given above, a tetraaza compound of formula can be reacted:
(VII)(VII)
Le composé tetraaza de formule (VII) qui sert de produit de départ pour cette synthèse peut être obtenu par des procédés classiques, par exemple par
réaction de condensation assistée par un métal de transition (template synthesis). Le produit est disponible aussi commercialement. The tetraaza compound of formula (VII) which serves as starting material for this synthesis can be obtained by conventional methods, for example by condensation reaction assisted by a transition metal (template synthesis). The product is also available commercially.
Lorsque le ligand tétraphosphonate répond à la formule : When the tetraphosphonate ligand corresponds to the formula:
(VIII)
dans laquelle R5 et R6 ont la signification donnée cidessus, on peut faire réagir un composé de formule : (VIII) in which R 5 and R 6 have the meaning given above, a compound of formula can be reacted:
(IX)
avec du phosphite de t ri i sop ropy l e pour former le composé de formule : (IX) with t ri i sop ropy le phosphite to form the compound of formula:
(X)
(X)
puis faire réagir le composé de formule (X) ainsi obtenu avec de l'acide chlorhydrique. then reacting the compound of formula (X) thus obtained with hydrochloric acid.
Cette synthèse correspond à la réaction d'Arbusov suivie d'une hydrolyse acide du tétraphosphonate obtenu.
Le composé de formule (IX) utilisé comme produit de départ pour cette synthèse peut être obtenu par des procédés classiques, par exemple par action du brome sur le 1,2,4,5, tétra méthy Ibenzène. Ce produit est disponible dans le commerce. This synthesis corresponds to the Arbusov reaction followed by an acid hydrolysis of the tetraphosphonate obtained. The compound of formula (IX) used as starting material for this synthesis can be obtained by conventional methods, for example by the action of bromine on 1,2,4,5, tetra methyl Ibenzene. This product is commercially available.
Dans les produits radiopharmaceut iques de l'invention, le choix des isotopes de Te, Y ou Re utilisés dépend en particulier de l'utilisation du produit. In the radiopharmaceutical products of the invention, the choice of the isotopes of Te, Y or Re used depends in particular on the use of the product.
Ainsi, lorsque le produit est destiné au diagnostic, par exemple par scintigraphie osseuse, on utilise le technétium 99m. Thus, when the product is intended for diagnosis, for example by bone scintigraphy, technetium 99m is used.
Lorsque le produit est destiné à la thérapie, on utilise l'yttrium 90 ou le rhénium 186 ou 188 qui ont des périodes plus longues et émettent des rayonnements plus efficaces pour des traitements thérapeutiques. When the product is intended for therapy, use is made of yttrium 90 or rhenium 186 or 188 which have longer periods and emit more effective radiation for therapeutic treatments.
L'invention a également pour objet une composition pour la préparation d'un produit radi opharmaceut ique comportant un isotope radioactif tel que le technétium, qui comprend : The subject of the invention is also a composition for the preparation of a radiopharmaceutical product comprising a radioactive isotope such as technetium, which comprises:
- au moins un l i g a nd c ho i s i p a rm i l e s a c i de s t é t r ap h o sp h on i que s répondant aux formules (I), (IV) et (V) données ci-dessus et leurs sels et esters pharmaceutiquement acceptables. - at least one l i g a nd c ho i s i p a rm i l e s a c i de s t é t r ap h o sp h on i que s corresponding to formulas (I), (IV) and (V) given above and their pharmaceutically acceptable salts and esters.
Dans certains cas, par exemple lorsque le produit radiopharmaceutique à préparer comporte du technétium ou du rhénium, la composition comprend en outre au moins un agent réducteur qui est destiné à réduire le technétium ou le rhénium lors de la préparation du complexe. In certain cases, for example when the radiopharmaceutical product to be prepared comprises technetium or rhenium, the composition also comprises at least one reducing agent which is intended to reduce technetium or rhenium during the preparation of the complex.
A titre d'exemples d'agents réducteurs susceptibles d'être utilisés, on peut citer les sels d'étain (II), de fer (II) et de chrome (II). As examples of reducing agents which may be used, mention may be made of the tin (II), iron (II) and chromium (II) salts.
Les sels pharmaceutiquement acceptables des
acides tétraphosphoniques utilisables dans l'invention peuvent être par exemple des sels de métaux alcalins, de métaux alcalinoterreux, de métaux lourds ou d'ammonium. Les sels alcalins tels que les sels de sodium, de potassium ou de lithium ainsi que les sels d'ammonium sont généralement préférés. The pharmaceutically acceptable salts of tetraphosphonic acids which can be used in the invention can be, for example, alkali metal, alkaline earth metal, heavy metal or ammonium salts. Alkaline salts such as sodium, potassium or lithium salts as well as ammonium salts are generally preferred.
Les esters pharmaceutiquement acceptables des acides tétraphosphoni ques de l'invention peuvent être des esters alkyliques inférieurs, comme par exemple les esters méthyliques, éthyliques, propyliques, isopropyliques, butyliques, isobutyliques et pentyliques. The pharmaceutically acceptable esters of the tetraphosphonic acids of the invention can be lower alkyl esters, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutylic and pentylic esters.
Dans la composition de l'invention on peut utiliser des sels ou des esters qui correspondent au remplacement de tous les atomes d'hydrogène des groupements PO3H 2 ou d'une partie seulement de ces atomes d'hydrogène. In the composition of the invention, it is possible to use salts or esters which correspond to the replacement of all the hydrogen atoms of the PO 3 H 2 groups or of only part of these hydrogen atoms.
On peut aussi utiliser des mélanges de sels, par exemple un mélange de sels de sodium et potassium. It is also possible to use mixtures of salts, for example a mixture of sodium and potassium salts.
Les sels d'étain, de fer ou de chrome utilisables comme agent réducteur peuvent être en particulier les chlorures et les sulfates. De préférence, on utilise le chlorure d'étain (II). The tin, iron or chromium salts which can be used as reducing agent can be in particular chlorides and sulfates. Preferably, tin (II) chloride is used.
Ils peuvent être présents sous la forme de sels hydratés, comme le dihydrate de chlorure d'étain. They can be present in the form of hydrated salts, such as tin chloride dihydrate.
On peut encore ajouter à la composition de l'invention un agent stabilisant, la composition contre l'oxydation et/ou l'hydrolyse. Cet agent a pour but d'empêcher l'oxydation de l'agent réducteur pendant le stockage de la composition et de prévenir par exemple la réoxydation du technétium ou du rhénium réduit apr è s fo rm at i o n du c omp l e x e . It is also possible to add to the composition of the invention a stabilizing agent, the composition against oxidation and / or hydrolysis. The purpose of this agent is to prevent the oxidation of the reducing agent during the storage of the composition and to prevent, for example, the reoxidation of technetium or reduced rhenium after formation of the compound.
L'agent stabilisant peut être choisi en particulier parmi l'acide ascorbique, l'acide gentisique, l'acide érythorbique, leurs sels et esters
pharmaceutiquement acceptables, et des mélanges de ceux-ci. The stabilizing agent can be chosen in particular from ascorbic acid, gentisic acid, erythorbic acid, their salts and esters. pharmaceutically acceptable, and mixtures thereof.
Dans la composition de l'invention, les teneurs en ligand tétraphosphonate, en agent réducteur et en agent stabilisant peuvent varier dans une large gamme. In the composition of the invention, the contents of tetraphosphonate ligand, of reducing agent and of stabilizing agent can vary within a wide range.
Ainsi, le rapport molaire de l'agent réducteur au ligand peut varier de 1/1 à 1/150. Généralement ce rapport molaire se situe dans la gamme de 1/1 à 1/10, de préférence de 1/1,5 à 1/4,5. Thus, the molar ratio of the reducing agent to the ligand can vary from 1/1 to 1/150. Generally this molar ratio is in the range of 1/1 to 1/10, preferably from 1 / 1.5 to 1 / 4.5.
La quantité d'agent stabilisant utilisée est généralement faible et de préférence ne dépasse pas 25% en poids. The amount of stabilizing agent used is generally small and preferably does not exceed 25% by weight.
A titre d'exemple, les compositions de l'invention peuvent comprendre : By way of example, the compositions of the invention can comprise:
- de 60 à 90% en poids d'acide tétraphosphonique et/ou de sel ou ester pharmaceutiquement acceptable de celui-ci, - from 60 to 90% by weight of tetraphosphonic acid and / or of a pharmaceutically acceptable salt or ester thereof,
- de 5 à 15% en poids d'agent réducteur, et - from 5 to 15% by weight of reducing agent, and
- de 0 à 25% en poids d'agent stabilisant. - from 0 to 25% by weight of stabilizing agent.
Les compositions de l'invention sont destinées à une injection intraveineuse à des êtres vivants et on doit donc utiliser des conditions appropriées de. fabrication et de mise en oeuvre pour obtenir des compositions convenablement stériles et apyrogènes. The compositions of the invention are intended for intravenous injection into living beings and therefore suitable conditions must be used. manufacturing and processing to obtain suitably sterile and pyrogen-free compositions.
On peut préparer ces compositions par un simple mélange à sec de l'agent réducteur, du ligand tétraphosphonate et du stabilisant. These compositions can be prepared by simple dry mixing of the reducing agent, the tetraphosphonate ligand and the stabilizer.
On peut aussi préparer les compositions de l'invention sous forme de solution aqueuse dans de l'eau stérile et apyrogène. Dans ce cas, on dissout le ligand t ét r a p h o s p h on i que , et éven t ue l l ement l ' a g e nt rédu c t eur et le ou les stabilisants dans une solution aqueuse en utilisant de l'eau désoxygénée. Cette composition peut être introduite dans un flacon et stockée sous azote lorsqu'elle contient un agent
réducteur pour réduire au minimum une oxydation inopportune de l'agent de réduction pendant le stockage. The compositions of the invention can also be prepared in the form of an aqueous solution in sterile, pyrogen-free water. In this case, the ligand is dissipated and, if necessary, the reducing age and the stabilizer (s) in an aqueous solution using deoxygenated water. This composition can be introduced into a bottle and stored under nitrogen when it contains an agent reducing agent to minimize untimely oxidation of the reducing agent during storage.
De préférence, les compositions de l'invention sont préparées sous forme lyophilisée. Dans ce cas après avoir dissous le ligand tétraphosphonate, et éventuellement l'agent réducteur et le stabilisant dans une solution aqueuse, on lyophilise la composition à l'aide d'un équipement classique. De même que précédemment on utilise de l'eau stérile désoxygénée pour la fabrication et l'on conserve le produit sous azote. Preferably, the compositions of the invention are prepared in lyophilized form. In this case, after having dissolved the tetraphosphonate ligand, and optionally the reducing agent and the stabilizer in an aqueous solution, the composition is lyophilized using conventional equipment. As before, sterile deoxygenated water is used for the manufacture and the product is stored under nitrogen.
Avant de lyophiliser la solution, on ajuste son pH à une valeur appropriée, généralement située dans la gamme de 5 à 7, de préférence à environ 6, par exemple par addition de soude ou d'acide chlorhydri que. Before lyophilizing the solution, its pH is adjusted to an appropriate value, generally situated in the range from 5 to 7, preferably to around 6, for example by addition of soda or hydrochloric acid.
Au moment de l'utilisation, on dissout la composition à l'aide d'une solution isotonique de l'isotope utilisé, par exemple de pertechnétate-99 m de métal alcalin ou d'ammonium provenant d'une source commerciale de technétium pour obtenir un produit radiopharmaceuti que pour la scintigraphie osseuse convenant pour une injection intraveineuse. L'injection peut être effectuée à partir de 15 minutes après l'addition de la solution d'isotope. At the time of use, the composition is dissolved using an isotonic solution of the isotope used, for example pertechnetate-99 m of alkali metal or ammonium from a commercial source of technetium to obtain a radiopharmaceuti that for bone scintigraphy suitable for intravenous injection. The injection can be carried out from 15 minutes after the addition of the isotope solution.
Lorsque l'isotope est le rhénium, on peut utiliser une solution de perrhénate de métal alcalin ou d'ammonium qui sera opportunément réduit à un état d'oxydation inférieur à +7. Lorsque l'isotope est l'yttrium, on peut utiliser une solution de nitrate, chlorure ou autre sel d'yttrium III. When the isotope is rhenium, an alkali metal or ammonium perrhenate solution can be used, which will expediently be reduced to an oxidation state of less than +7. When the isotope is yttrium, a solution of nitrate, chloride or other yttrium III salt can be used.
Pour l'injection du produit radiopharmaceutique les quantités de ligands tétraphosphonates peuvent aller de 0,1 à 10 milligrammes par examen en fonction du ligand tétraphosphonate utilisé et de sa toxicité. La quantité d'agent réducteur associée peut être de
de 0,01 à 2,5 milligrammes. For the injection of the radiopharmaceutical, the amounts of tetraphosphonate ligands can range from 0.1 to 10 milligrams per examination depending on the tetraphosphonate ligand used and its toxicity. The amount of associated reducing agent can be from 0.01 to 2.5 milligrams.
Généralement, on obtient des résultats satisfaisants en utilisant des quantités de ligands tétraphosphonates allant de 0,1 à 5 milligrammes pour un adulte pesant 50 à 100 kilogrammes. Generally, satisfactory results are obtained by using amounts of tetraphosphonate ligands ranging from 0.1 to 5 milligrams for an adult weighing 50 to 100 kilograms.
La dose totale de technétium pour un examen précis du squelette se situe généralement entre 370et 740 Mbq (10 à 20 millicuries). The total dose of technetium for a precise examination of the skeleton is generally between 370 and 740 Mbq (10 to 20 millicuries).
Après l'administration du complexe de technétium, on peut effectuer un examen satisfaisant du squelette dans un délai de 1h à 4h en obtenant un bon contraste, des images nettes et une excellente détection des lésions. After administration of the technetium complex, a satisfactory examination of the skeleton can be carried out within 1 to 4 hours, obtaining good contrast, clear images and excellent detection of lesions.
L'invention sera mieux comprise à la lecture des exemples suivants donnés bien entendu à titre illustratif et non limitatif. The invention will be better understood on reading the following examples given, of course, by way of illustration and not limitation.
EXEMPLE 1 : Préparation de l'acide tétraaza-1,4,8,11 cyclotétradécane tét ra (méthylènephosphoni que)-1,4,8,11. (TTMP) EXAMPLE 1 Preparation of tetraaza-1,4,8,11 cyclotetradecane tét ra (methylenephosphoni que) -1,4,8,11 acid. (TTMP)
Ce composé correspond à la formule (IV) donnée ci-dessus. This compound corresponds to formula (IV) given above.
On prépare cet acide tét raphosphonique par la réaction de MANNICH qui correspond au schéma réactionnel suivant : This tet raphosphonic acid is prepared by the MANNICH reaction which corresponds to the following reaction scheme:
A 10 ml d'eau, placés dans un ballon à trois cols, équipé d'un thermomètre, d'un réfrigérant et d'une ampoule à pression compensée, on additionne
goutte à goutte et sous agitation 8.10-2 mole (11g) de trichlorure de phosphore PCI3, tout en maintenant la température du mélange réactionnel au-dessous de 5°C au cours de l'addition. To 10 ml of water, placed in a three-necked flask, equipped with a thermometer, a condenser and a pressure-compensated ampoule, the following is added dropwise and with stirring 8.10 -2 mole (11g) of phosphorus trichloride PCI 3 , while maintaining the temperature of the reaction mixture below 5 ° C during the addition.
Au mélange réactionnel obtenu précédemment, on ajoute 1,85.10 mole (3,72g) de cyclam H), 7ml d'une solution aqueuse d'acide eh lorhydrique à 37% et 7 ml d'eau ; au mélange réactionnel porté au reflux (104°C), on ajoute Lentement et sous forte agitation 9.10-2 mole de formaldéhyde (7ml d'une solution aqueuse à 37%). On observe après une heure de réaction la formation d'un précipité blanc ; la réaction est poursuivie à 100°C pendant 12 heures. To the reaction mixture obtained above, 1.85.10 mol (3.72 g) of cyclam H), 7 ml of an aqueous solution of hydrofluoric acid at 37% and 7 ml of water are added; to the reaction mixture brought to reflux (104 ° C.), 9.10 -2 mol of formaldehyde (7 ml of a 37% aqueous solution) are added slowly and with vigorous stirring. After one hour of reaction, the formation of a white precipitate is observed; the reaction is continued at 100 ° C for 12 hours.
L'acide 2 est récupéré par filtration, lavé à l'eau et recristallisé dans l'eau (la dissolution est réalisée au reflux par addition de NaOH et le pH est ramené à 1,5 par HCl avant précipitation). The acid 2 is recovered by filtration, washed with water and recrystallized from water (the dissolution is carried out at reflux by addition of NaOH and the pH is brought back to 1.5 by HCl before precipitation).
On obtient ainsi un solide cristallisé blanc, ayant un point de fusion supérieur à 250°C et la structure suivante : A white crystallized solid is thus obtained, having a melting point above 250 ° C and the following structure:
Sa masse molaire qui correspond à l'acide Its molar mass which corresponds to the acid
C14H36O12N4, 2H2O est de 612,45. C 14 H 36 O 12 N 4 , 2H 2 O is 612.45.
Les caractéristiques de ce composé sont les suivantes : The characteristics of this compound are as follows:
Analyse élémentaire :
Calculée Elementary analysis: Calculated
Trouvée Found
Résonance magnétique nucléaire Nuclear magnetic resonance
- RMN 31P non découplé - 31 P NMR not decoupled
solvant D2O/NaOD solvent D 2 O / NaOD
δ= 13,59 J = 11,5 Hz - RMN 1H δ = 13.59 J = 11.5 Hz - 1 H NMR
δN-CH2-C-N = 3,52 ppm δN-CH2-C-CN = 3,42 ppm δN-CH2-P = 3,18 ppm = 11,7 Hz δC-CH2-C = 2,35 ppm RMN 13C δN-CH 2 -CN = 3.52 ppm δN-CH 2 -C-CN = 3.42 ppm δN-CH 2 -P = 3.18 ppm = 11.7 Hz δC-CH 2 -C = 2.35 ppm 13 C NMR
= 29,5 ppm = 29.5 ppm
5C-C-C 5 CCC
δN-C-C-C-N et δN-C-C-N = 57,8 et 61,4 ppm avec JP-C = 6,5 et 5,7 Hz δP-C = 63,15 ppm J = 140 Hz δ NCCCN and δ NCCN = 57.8 and 61.4 ppm with J PC = 6.5 and 5.7 Hz δ PC = 63.15 ppm J = 140 Hz
Infrarouge : Infrared:
entre 2200 et 3450 cm-1 : et vNH between 2200 and 3450 cm -1 : and v NH
vP=O = 1170 cm-1 v P = O = 1170 cm -1
EXEMPLE 2 : Préparation de l'acide benzène tétraméthylène phosphonique de formule (V) (BTMP). EXAMPLE 2 Preparation of benzene tetramethylene phosphonic acid of formula (V) (BTMP).
On réalise la synthèse de cet acide par la réaction d'ARBUSOV du phosphite de triisopropyle sur le tétrakisbromométhyl-1,2,4,5 benzène suivie d'une
hydrolyse acide du tétraphosphonate ainsi obtenu. The synthesis of this acid is carried out by the ARBUSOV reaction of triisopropyl phosphite on tetrakisbromomethyl-1,2,4,5 benzene followed by a acid hydrolysis of the tetraphosphonate thus obtained.
a) Préparation du benzènetétraméthyl ènep ho sp h onat e d'octaisopropyle. a) Preparation of benzenetetramethyl ene ho sp h onate of octaisopropyl.
On porte au reflux pendant 6 heures à 120°C dans un ballon à trois cols équipé d'un régrigérant et d'un thermomètre un mélange de 0,022 mole (10g) de tétrakisbromométhyl-1,2,4,5 benzène et de 0,096 mole (20 g) de phosphite de triisopropyle. A mixture of 0.022 mole (10g) of tetrakisbromomethyl-1,2,4,5 benzene and 0.096 mole is brought to reflux for 6 hours at 120 ° C. in a three-necked flask equipped with a condenser and a thermometer. (20 g) triisopropyl phosphite.
En fin de réaction on élimine l'excès de phosphite au rotavapor. At the end of the reaction, the excess phosphite is eliminated on a rotary evaporator.
b) Préparation de l'acide benzène tétraméthylène- phosphonique-1,2,4,5. b) Preparation of benzene tetramethylene phosphonic acid-1,2,4,5.
Au produit brut obtenu précédemment, placé dans un tricol équipé d'un thermomètre, d'un réfrigérant surmonté d'un piège à HCl, on ajoute 100 ml d'acide chlorhydrique à 37%. On porte au reflux le mélange réactionnel pendant 16 heures et on purifie l'acide obtenu par recristallisation dans l'eau comme dans l'exemple 1. To the raw product obtained previously, placed in a three-necked flask equipped with a thermometer, with a condenser surmounted by an HCl trap, 100 ml of 37% hydrochloric acid are added. The reaction mixture is brought to reflux for 16 hours and the acid obtained is purified by recrystallization from water as in Example 1.
On obtient ainsi un solide cristallisé blanc, ayant un point de fusion supérieur à 250°C répondant à la formule (V). Ce composé contient une quantité de sodium variable entre 2 et 5%. A white crystalline solid is thus obtained, having a melting point above 250 ° C corresponding to formula (V). This compound contains an amount of sodium varying between 2 and 5%.
La masse moléculaire qui correspond à l'acide libre C10H18O12P4 est de 454,12. The molecular mass which corresponds to the free acid C 10 H 18 O 12 P 4 is 454.12.
Les caractéristiques de cet acide sont les suivantes. The characteristics of this acid are as follows.
Analyse élémentaire :
Elementary analysis:
Résonance magnétique nucléaire : Nuclear magnetic resonance:
- RMN31P { 1H} sur appareil fonctionnant à 80 MHz pour le proton - 31 P NMR { 1 H} on a device operating at 80 MHz for the proton
solvant : D2O/NaOD
δ= 20 ppm solvent: D 2 O / NaOD δ = 20 ppm
- RMN31P non dé c oup l é - 31 P NMR not broken down
solvant : DMSO solvent: DMSO
δ23,93 ppm JP-CH = 18 Hz δ23.93 ppm J P-CH = 18 Hz
- RMN1H - 1 H NMR
δ = 3,7 ppm J= 18,3 Hz δ = 3.7 ppm J = 18.3 Hz
δΦH = 7,8 ppm - RMN13C δΦH = 7.8 ppm - 13 C NMR
= 34,12 ppm JP-C = 128,2 Hz= 34.12 ppm J PC = 128.2 Hz
δΦ = 134,24 et 132,85 ppm δΦ = 134.24 and 132.85 ppm
Infrarouge Infrared
massif entre 2200 et 3100 cm-1 vPO3H2 massive between 2200 and 3100 cm -1 vPO 3 H 2
vP=O = 1160 cm v P = O = 1160 cm
EXEMPLE 3 : Préparation d'une composition contenant duEXAMPLE 3 Preparation of a composition containing
TTMP pour la scintigraphie osseuse. TTMP for bone scintigraphy.
On dissout 5 mg de TTMP exprimé en masse d'acide phosphonique libre après dosage de l'eau et du sodium éventuellement présents, obtenu dans L'exemple 1 dans 2 ml de solution de chlorure de sodium à 0,9% et on amène le pH de la solution à environ 7 par une solution d'hydroxyde de sodium 0,1 N. 5 mg of TTMP, expressed in mass of free phosphonic acid, after determination of the water and of the sodium optionally present, obtained in Example 1, are dissolved in 2 ml of 0.9% sodium chloride solution and the pH of the solution at about 7 with 0.1 N sodium hydroxide solution
On ajoute 0,75 mg de chlorure d'étain (II) dihydraté dissous dans une solution d'acide chlorhydrique 0,01 N (solution à 7,5 mg/ml), et 1,25 mg d'acide ascorbique à partir d'une solution aqueuse à 12,5 mg/ml. Le pH est amené à des valeurs comprises entre pH5 et 7 par addition de base ou d'acide. Le flacon est bouché et purgé 15 minutes par balayage d* azote. 0.75 mg of tin (II) chloride dihydrate dissolved in 0.01 N hydrochloric acid solution (7.5 mg / ml solution) is added, and 1.25 mg of ascorbic acid from '' an aqueous solution at 12.5 mg / ml. The pH is brought to values between pH5 and 7 by addition of base or acid. The bottle is capped and purged for 15 minutes by flushing with nitrogen.
On ajoute ensuite 0,5 à 5 ml de solution de
pertechnétate de sodium (99 mTc) et on laisse agir à température ambiante pendant 15 minutes. 0.5 to 5 ml of solution are then added. sodium pertechnetate (99 mTc) and allowed to act at room temperature for 15 minutes.
L'analyse chromatographi que sur silicagel ITL- Chromatographic analysis on ITL-silica gel
SG développée en butanone-2 révèle une quantité de pertechnétate libre inférieure à 5%. Cette valeur reste stable pendant au moins 6 heures. SG developed in butanone-2 reveals an amount of free pertechnetate less than 5%. This value remains stable for at least 6 hours.
EXEMPLE 4 : Préparation d'une composition pour scintigraphie osseuse contenant du TTMP. EXAMPLE 4 Preparation of a composition for bone scintigraphy containing TTMP.
Dans un réacteur maintenu sous atmosphère inerte, on introduit 70 ml d'eau désaérée, 10 ml de solution de NaOH 0,1 N et 200 mg de TTMP (exprimé en masse d'acide phosphonique libre après dosage de l'eau et du sodium éventuellement présents). Après dissolution le pH est amené à environ 7-7,5. 70 ml of deaerated water, 10 ml of 0.1 N NaOH solution and 200 mg of TTMP (expressed in mass of free phosphonic acid after determination of water and sodium) are introduced into a reactor maintained under an inert atmosphere. possibly present). After dissolution the pH is brought to about 7-7.5.
On ajoute 30 mg de chlorure d'étain (II) dihydraté et 50 mg d'acide ascorbique. 30 mg of tin (II) chloride dihydrate and 50 mg of ascorbic acid are added.
Après dissolution complète, on traite séparément différentes solutions obtenues de la même façon pour ajuster leur pH à des valeurs de 5,0-6,0 ou 7,0 par addition de soude ou d'acide chlorhydrique et le volume de chaque solution est amené à 100 ml par de l'eau. After complete dissolution, different solutions obtained are treated separately in the same way to adjust their pH to values of 5.0-6.0 or 7.0 by addition of sodium hydroxide or hydrochloric acid and the volume of each solution is brought 100 ml with water.
On distribue alors les solutions dans des flacons sous azote en introduisant dans chaque flacon 1 ml de solution pour chaque pH et on procède à l'opération de lyophilisation du produit dans les flacons. The solutions are then distributed in bottles under nitrogen by introducing into each bottle 1 ml of solution for each pH and the product is lyophilized in the bottles.
EXEMPLE 5 : Préparation d'une composition pour scintigraphie osseuse à base d'acide benzène tétra (méthylène phosphonique)-1,2,4,5 (BTMP). EXAMPLE 5 Preparation of a composition for bone scintigraphy based on benzene tetra acid (methylene phosphonic) -1,2,4,5 (BTMP).
On suit le même mode opératoire que dans l'exemple 3 pour préparer cette composition en utilisant 5 mg de BTMP (exprimé en masse d'acide phosphonique libre après dosage de l'eau et du sodium éventuellement présents) au lieu de 5 mg de TTMP.
L'analyse chromatographique réalisée dans les mêmes conditions que celles de l'exemple 3 montre que la quantité de pertechnétate libre est inférieure à 5% et que cette valeur reste stable pendant au moins 6 heures. The same procedure is followed as in Example 3 to prepare this composition using 5 mg of BTMP (expressed in mass of free phosphonic acid after determination of the water and of the sodium which may be present) instead of 5 mg of TTMP . Chromatographic analysis carried out under the same conditions as those of Example 3 shows that the amount of free pertechnetate is less than 5% and that this value remains stable for at least 6 hours.
EXEMPLE 6 : Préparation d'une composition pour scintigrahie osseuse contenant du BTMP. EXAMPLE 6 Preparation of a composition for bone scintigray containing BTMP.
On suit le même mode o p é r a t o i r e que d a n s l ' e x e mp l e 4 pou r p r é p a r e r d e s solutions contenant du BTMP, du chlorure d'étain II (dihydraté) et de l'acide ascorbique en utilisant 200 mg de BTMP exprimé en masse d'acide phosphonique libre après dosage de l'eau et du sodium éventuellement présents. On ajuste également Le pH des solutions à des valeurs de 5,6 ou 7 puis on distribue les solutions dans des flacons (1 ml de solution par flacon) sous azote, et on Lyophilise. The same operating mode is followed as in example 4 for preparing solutions containing BTMP, tin chloride II (dihydrate) and ascorbic acid using 200 mg of BTMP expressed as mass of free phosphonic acid after dosing of water and sodium which may be present. The pH of the solutions is also adjusted to values of 5.6 or 7, then the solutions are distributed in vials (1 ml of solution per vial) under nitrogen, and lyophilized.
EXEMPLE 7: Préparation d'une solution pour la scintigraphie osseuse contenant du TTMP. EXAMPLE 7 Preparation of a solution for bone scintigraphy containing TTMP.
On ajoute 0,5 ml à 5 ml d'une solution de pertechnétate de sodium (99 mTC) contenant 2 μCurie à 100 mCurie (74 kBq à 3,7 GBq) à un flacon contenant sous forme lyophilisée le mélange de TTMP, de chlorure daétain et d'acide ascorbique obtenu dans l'exemple 4 à partir de la solution à pH 6. On agite le flacon pour dissoudre le lyophilisât et la réaction de réduction du pertechnétate a Lieu en 15 minutes. La solution obtenue reste stable pendant au moins 6 heures. 0.5 ml to 5 ml of a sodium pertechnetate solution (99 mTC) containing 2 μCurie at 100 mCurie (74 kBq to 3.7 GBq) are added to a flask containing the mixture of TTMP and chloride in lyophilized form of tin and ascorbic acid obtained in Example 4 from the pH 6 solution. The bottle is shaken to dissolve the lyophilisate and the pertechnetate reduction reaction takes place in 15 minutes. The solution obtained remains stable for at least 6 hours.
EXEMPLE 8: Préparation d'une solution pour la scintigraphie osseuse contenant du BTMP. EXAMPLE 8 Preparation of a solution for bone scintigraphy containing BTMP.
On suit le même mode opératoire que dans l'exemple 7 mais en utilisant les flacons contenant le mélange lyophilisé de BTMP, de chlorure d'étain et d'acide ascorbique obtenu dans l'exemple 6. Comme précédemment on constate que le produit formé reste stable pendant 6 heures.
EXEMPLE 9 The same procedure is followed as in Example 7, but using the bottles containing the lyophilized mixture of BTMP, tin chloride and ascorbic acid obtained in Example 6. As above, it can be seen that the product formed remains stable for 6 hours. EXAMPLE 9
Dans cet exemple on teste les propriétés de la composition obtenue dans l'exemple 7 à partir des flacons lyophilisés ayant avant lyophilisation un pH de 6 pour la scintigraphie. In this example, the properties of the composition obtained in Example 7 are tested from the lyophilized bottles having, before lyophilization, a pH of 6 for scintigraphy.
Pour cet essai, on utilise des rats pesant en moyenne 200±20 g et on leur injecte par voie intraveineuse les produits préparés dans l'exemple 7 à raison de 0,3 mg d'acide tét raphosphoni que par kg de masse corporelle, ce qui correspond à 0,15 ml des produits obtenus dans l'exemple 7 par addition de 5 ml de solution de pertechnétate de sodium au flacon lyophilise. For this test, rats weighing on average 200 ± 20 g are used and the products prepared in Example 7 are injected intravenously with 0.3 mg of tet raphosphoni acid per kg of body mass, which corresponds to 0.15 ml of the products obtained in Example 7 by adding 5 ml of sodium pertechnetate solution to the lyophilized bottle.
Les rats sont ensuite sacrifiés par groupe de trois, 30 minutes, 60 minutes, 120 minutes ou 180 minutes après l'injection. Les différents organes sont prélevés et l'on détermine leur radioactivité. The rats are then sacrificed in groups of three, 30 minutes, 60 minutes, 120 minutes or 180 minutes after the injection. The different organs are removed and their radioactivity is determined.
Les résultats obtenus sont donnés dans le tableau 1 qui suit et exprimés en % de la radioactivité retrouvée dans l'organe après prélèvement, la radioactivité injectée étant de 500 μCurie (18,5 MBq). The results obtained are given in Table 1 below and expressed as a% of the radioactivity found in the organ after sampling, the radioactivity injected being 500 μCurie (18.5 MBq).
On détermine également la radioactivité des urines en fonction du temps par une expérience d'acquisition à la gamma caméra. The radioactivity of the urine is also determined as a function of time by a gamma camera acquisition experiment.
Les résultats donnés dans le tableau 1 montrent que la radioactivité se trouve de façon prépondérante dans le squelette et que la clairance sanguine est rapide. The results given in Table 1 show that radioactivity is found predominantly in the skeleton and that the blood clearance is rapid.
EXEMPLE 10 EXAMPLE 10
Dans cet exemple on teste les propriétés du produit obtenu dans l'exemple 7 en réalisant des expériences chez le rat. In this example, the properties of the product obtained in Example 7 are tested by carrying out experiments in rats.
On utilise également des rats mâles ayant un poids de 200 ± 20 g et on leur injecte le produit préparé dans l'exemple 7 à partir des flacons lyophilisés à pH 6 à raison de 0,3 mg par kg. On contrôle la répartition de la radioactivité dans le
corps du rat en fonction du temps par acquisition dynamique à la gamma caméra en effectuant les mesures sur l'animal anesthésié par le penthobarbital, la radioactivité injectée étant de 500 μCurie (18,5 MBq). Male rats weighing 200 ± 20 g are also used and the product prepared in Example 7 is injected into them from lyophilized flasks at pH 6 at a rate of 0.3 mg per kg. The distribution of radioactivity in the body of the rat as a function of time by dynamic acquisition with the gamma camera by carrying out the measurements on the animal anesthetized with penthobarbital, the radioactivity injected being 500 μCurie (18.5 MBq).
Les résultats obtenus, exprimés en pourcentage de radioactivité dans les zones examinées par rapport à la radioactivité de l'animal entier, sont donnés dans le tableau 2 qui suit. Dans ce tableau on a indiqué également les pourcentages de radioactivité mesurés dans les cartilages après avoir exclu la radioactivité présente dans la vessie par interposition d'un cache en plomb ou par prélèvement de la vessie. The results obtained, expressed as a percentage of radioactivity in the areas examined relative to the radioactivity of the whole animal, are given in Table 2 which follows. This table also indicates the percentages of radioactivity measured in the cartilages after excluding the radioactivity present in the bladder by interposing a lead cover or by removing the bladder.
Les résultats du tableau 2 montrent également que la clairance sanguine est rapide. The results in Table 2 also show that the blood clearance is rapid.
EXEMPLE 11. EXAMPLE 11.
Dans cet exemple, on teste les propriétés du produit obtenu dans l'exemple 8 chez le rat. Dans ce cas, on suit le même mode opératoire que dans l'exemple 9 mais en injectant 0,3 mg de BTMP (Sn) 99m Te par kg de poids du corps, c'est-à-dire le produit obtenu dans l'exemple 8 à partir des flacons lyophilisés à pH=6. In this example, the properties of the product obtained in Example 8 are tested in rats. In this case, the same procedure is followed as in Example 9 but by injecting 0.3 mg of BTMP (Sn) 99m Te per kg of body weight, that is to say the product obtained in the Example 8 from the lyophilized bottles at pH = 6.
Les résultats obtenus, donnés dans le tableau 3, montrent que le produit se concentre plus spécialement dans le squelette et que la clairance sanguine est rapide. Par ailleurs, on remarque que la radioactivité dans le squelette au bout de 60 minutes est équivalente à celle obtenue après 120 minutes ; ainsi le produit se fixe rapidement sur les tissus osseux. The results obtained, given in table 3, show that the product concentrates more especially in the skeleton and that the blood clearance is rapid. Furthermore, we note that the radioactivity in the skeleton after 60 minutes is equivalent to that obtained after 120 minutes; thus the product quickly binds to the bone tissue.
EXEMPLE 12. EXAMPLE 12.
Dans cet exemple, on suit le même mode opératoire que dans l'exemple 10 pour tester les propriétés du BTMP (Sn)99m Te obtenu dans l'exemple 8 à partir des flacons à pH=6. Les résultats obtenus sont donnés dans le tableau 4, la dose injectée étant également de 0,3 mg par kilogramme de poids corporel.
EXEMPLE COMPARATIF 1. In this example, the same procedure is followed as in Example 10 to test the properties of the BTMP (Sn) 99m Te obtained in Example 8 from the vials at pH = 6. The results obtained are given in Table 4, the dose injected also being 0.3 mg per kilogram of body weight. COMPARATIVE EXAMPLE 1.
Dans cet exemple, on suit le même mode opératoire que dans l'exemple 9 pour tester les propriétés pour la scintigraphie osseuse du produit de L'art antérieur HMDP (Sn)99m Te en injectant au rat 0,1 mg de HMDP par kilogramme de masse corporelle. In this example, the same procedure is followed as in Example 9 to test the properties for bone scintigraphy of the product of the prior art HMDP (Sn) 99m Te by injecting the rat with 0.1 mg of HMDP per kilogram of body mass.
Le HMDP a été obtenu à partir de flacons contenant 2 mg de HMDP, 0,3 mg de chlorure d'étain SnCl2, 2H2O et 0,5 mg d'acide ascorbique, en ajoutant aux flacons 5 ml d'une solution de pertechnétate de sodium. Les résultats obtenus sont donnés dans le tableau 5. HMDP was obtained from vials containing 2 mg of HMDP, 0.3 mg of tin chloride SnCl 2 , 2H 2 O and 0.5 mg of ascorbic acid, by adding 5 ml of a solution to the vials sodium pertechnetate. The results obtained are given in Table 5.
EXEMPLE COMPARATIF 2 COMPARATIVE EXAMPLE 2
Dans cet exemple on suit le même mode opératoire que dans l'exemple 10 pour tester les propriétés du HMDP (Sn)99m Te provenant de flacons identiques à ceux utilisés dans l'exemple comparatif 1, en injectant le produit à une dose de 0,1 mg par kilogramme de masse corporelle. In this example, the same procedure is followed as in Example 10 to test the properties of HMDP (Sn) 99m Te from bottles identical to those used in Comparative Example 1, by injecting the product at a dose of 0, 1 mg per kilogram of body mass.
Les résultats obtenus sont donnés dans le tableau 6. The results obtained are given in Table 6.
Dans le tableau 7, on a reporté les rapports os/sang et les rapports os/foie obtenus à partir des résultats des exemples 9 et 11 et de l'exemple comparatif 1, en fonction du temps pour les différents composés testés. In Table 7, the bone / blood ratios and the bone / liver ratios obtained from the results of Examples 9 and 11 and Comparative Example 1 are plotted as a function of time for the various compounds tested.
Au vu de ce tableau, on constate que 60 minutes après l'injection, les rapports os/sang et os/foie sont bien meilleurs avec les composés de l'invention qu'avec le composé de l'art antérieur.
In view of this table, it can be seen that 60 minutes after the injection, the bone / blood and bone / liver ratios are much better with the compounds of the invention than with the compound of the prior art.
Claims
1. Produit radiopharmaceutique, caractérisé en ce qu'il est constitué par un complexe de technétium, de rhénium ou d'yttrium comportant un ligand tétraphosphonate choisi parmi les acides tétraphosphoniques répondant à la formule : 1. Radiopharmaceutical product, characterized in that it consists of a technetium, rhenium or yttrium complex comprising a tetraphosphonate ligand chosen from tetraphosphonic acids corresponding to the formula:
(I) 
(I)
dans laquelle est un radical cyclique répondant aux formules 
in which is a cyclic radical corresponding to the formulas
(II) ou 
(II) or
dans laquelle R7 et R8 qui sont identiques ou différents représentent un atome d'hydrogène ou un radical alkyle ou aryle, les radicaux de formule (CH2)n in which R 7 and R 8 which are identical or different represent a hydrogen atom or an alkyl or aryl radical, the radicals of formula (CH 2 ) n
COOR9 dans laquelle n est un nombre entier de 1 à 5 et R9 représente un atome d'hydrogène, NH4, un métal physiologiquement acceptable M1/v avec v représentant la valence du métal M ou un radical alkyle, les radicaux de formule 
COOR 9 in which n is an integer from 1 to 5 and R 9 represents a hydrogen atom, NH 4 , a physiologically acceptable metal M 1 / v with v representing the valence of the metal M or an alkyl radical, the radicals of formula
dans laquelle n, R7 et R8 ont la signification donnée ci-dessus et les radicaux de formule SO3R9 dans laquelle R9 a la signification donnée ci-dessus, et les sels et esters pharmaceutiquement acceptables de ces acides tétraphosphoniques. in which n, R 7 and R 8 have the meaning given above and the radicals of formula SO 3 R 9 in which R 9 has the meaning given above, and the pharmaceutically acceptable salts and esters of these tetraphosphonic acids.
2. Produit radiopharmaceutique selon la revendication 1, caractérisé en ce que le ligand tétraphosphonate est l'acide tétraphosphonique répondant à la formule : 2. radiopharmaceutical product according to claim 1, characterized in that the tetraphosphonate ligand is tetraphosphonic acid corresponding to the formula:
(IV) 
(IV)
ou l'un de ses sels et esters pharmaceutiquement acceptables. or one of its pharmaceutically acceptable salts and esters.
3. Produit radiopharmaceutique selon la revendication 1, caractérisé en ce que le ligand tétraphosphonate est l'acide tétraphosphonique répondant à la formule : (V) 
3. radiopharmaceutical product according to claim 1, characterized in that the tetraphosphonate ligand is tetraphosphonic acid corresponding to the formula: (V)
ou l'un de ses sels et esters pharmaceutiquement acceptables. or one of its pharmaceutically acceptable salts and esters.
4. Produit radi opharmaceutique pour le diagnostic selon l'une quelconque des revendications 1 à 3, caractérisé en ce qu'il est constitué par un complexe de technétium Tc-99m. 4. radiopharmaceutical product for diagnosis according to any one of claims 1 to 3, characterized in that it consists of a technetium complex Tc-99m.
5. Produit radiopharmaceutique pour la thérapie selon l'une quelconque des revendications 1 à 3, caractérisé en ce qu'il est constitué par un complexe d'yttrium 90 ou de rhénium 186 ou 188. 5. A radiopharmaceutical for therapy according to any one of claims 1 to 3, characterized in that it consists of a yttrium 90 or rhenium 186 or 188 complex.
6. Composition pour la préparation d'un produit radiopharmaceutique comportant un isotope radioactif, caractérisée en ce qu'elle comprend : 6. Composition for the preparation of a radiopharmaceutical product comprising a radioactive isotope, characterized in that it comprises:
- au moins un ligand choisi parmi les acides tét raphosphoniques répondant à la formule : - at least one ligand chosen from tet raphosphonic acids corresponding to the formula:
(I) 
(I)
dans laquelle est un radical cyclique répondant aux formules : 
( III) 
dans lesquelles m et n, qui peuvent être identiques ou différents, sont des nombres entiers allant de 2 à 4, et R1, R2, R3, R4, R5 et R6, qui peuvent être identiques ou différents, représentent un atome d'hydrogène ou un radical choisi parmi les radicaux alkyle. Les radicaux de formule /in which is a cyclic radical corresponding to the formulas: (III) in which m and n, which may be identical or different, are integers ranging from 2 to 4, and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , which may be identical or different, represent a hydrogen atom or a radical chosen from alkyl radicals. The radicals of formula /
dans laquelle R7 et R8 qui sont identiques ou différents représentent un atome d'hydrogène ou un radical alkyle ou aryle. Les radicaux de formule (CH2)n in which R 7 and R 8 which are identical or different represent a hydrogen atom or an alkyl or aryl radical. The radicals of formula (CH 2 ) n
COOR9 dans laquelle n est un nombre entier de 1 à 5 et R9 représente un atome d'hydrogène, NH4, un métal physiologiquement acceptable M1/v avec v représentant la valence du métal M ou un radical alkyle. Les radicaux de formule 
dans laquelle n, R7 et R8 ont la signification donnée ci-dessus et les radicaux de formule SO3R9 dans laquelle R9 a la signification donnée ci-dessus, et les sels et esters pharmaceutiquement acceptables de ces acides tét raphosphoniques, et COOR 9 in which n is an integer from 1 to 5 and R 9 represents a hydrogen atom, NH 4 , a physiologically acceptable metal M 1 / v with v representing the valence of the metal M or an alkyl radical. The radicals of formula in which n, R 7 and R 8 have the meaning given above and the radicals of formula SO 3 R 9 in which R 9 has the meaning given above, and the pharmaceutically acceptable salts and esters of these tet raphosphonic acids, and
- au moins un agent réducteur. - at least one reducing agent.
7. Composition selon la revendication 6, caractérisée en ce que le ligand est choisi parmi l'acide tetraphosphonique répondant à la formule : 7. Composition according to Claim 6, characterized in that the ligand is chosen from tetraphosphonic acid corresponding to the formula:
(IV) 
(IV)
et ses sels et esters pharmaceutiquement acceptables. and its pharmaceutically acceptable salts and esters.
8. Composition selon la revendication 6, caractérisée en ce que le ligand tétraphosphonate est choisi parmi l'acide tetraphosphonique répondant à la formule : 8. Composition according to claim 6, characterized in that the tetraphosphonate ligand is chosen from tetraphosphonic acid corresponding to the formula:
(V) 
(V)
et ses sels et esters pharmaceutiquement acceptables. and its pharmaceutically acceptable salts and esters.
9. Composition selon l'une quelconque des revendications 6 à 8, caractérisée en ce qu'elle comprend de plus un agent stabilisant. 9. Composition according to any one of claims 6 to 8, characterized in that it further comprises a stabilizing agent.
10. Composition selon l'une quelconque des revendications 6 à 8, caractérisée en ce que l'agent réducteur est choisi parmi les sels d'étain (II), de fer (II) et de chrome (II). 10. Composition according to any one of claims 6 to 8, characterized in that the reducing agent is chosen from tin (II), iron (II) and chromium (II) salts.
11. Composition selon la revendication 10, caractérisée en ce que l'agent réducteur est le chlorure d'étain (II). 11. Composition according to claim 10, characterized in that the reducing agent is tin chloride (II).
12. Composition selon la revendication 9, caractérisée en ce que l'agent stabilisant est choisi parmi l'acide ascorbique, l'acide gentisique, l'acide érythorbique, leurs sels et esters pharmaceutiquement acceptables et des mélanges de ceux-ci. 12. Composition according to claim 9, characterized in that the stabilizing agent is chosen from ascorbic acid, gentisic acid, erythorbic acid, their salts and esters pharmaceutically acceptable and mixtures thereof.
13. Composition selon la revendication 9, caractérisée en ce qu'elle comprend : 13. Composition according to claim 9, characterized in that it comprises:
- 60 à 90% en poids d'acide tetraphosphonique et/ou de sel ou ester pharmaceutiquement acceptable de celui-ci, - 60 to 90% by weight of tetraphosphonic acid and / or of a pharmaceutically acceptable salt or ester thereof,
- 5 à 15% en poids d'agent réducteur, et - 5 to 15% by weight of reducing agent, and
- 0 à 25% en poids d'agent stabilisant. - 0 to 25% by weight of stabilizing agent.
14. Composition selon l'une quelconque des revendications 6 à 13, caractérisée en ce que l'isotope radioactif est le technétium -99m. 14. Composition according to any one of claims 6 to 13, characterized in that the radioactive isotope is technetium -99m.
15. Procédé de préparation d'un ligand tétraphosphonate de formule : 15. Process for the preparation of a tetraphosphonate ligand of formula:
(VIII) 
dans laquelle R5 et R6 ont la signification donnée dans la revendication 1, caractérisé en ce qu'il consiste à faire réagir un composé de formule : (VIII) in which R 5 and R 6 have the meaning given in claim 1, characterized in that it consists in reacting a compound of formula:
(IX) 
avec du phosphite de triisopropy le pour former le composé de formule : 
(IX) with triisopropy le phosphite to form the compound of formula:
- à faire réagir le composé de formule (X) ainsi obtenu avec de l'acide ch lorhydrique. - reacting the compound of formula (X) thus obtained with hydrochloric acid.
16. Produit radiopharmaceutique obtenu en ajoutant du pertechnétate de métal alcalin ou d'ammonium à la composition selon l'une quelconque des revendications 6 à 13. 16. A radiopharmaceutical product obtained by adding alkali metal or ammonium pertechnetate to the composition according to any one of claims 6 to 13.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR88/12099 | 1988-09-16 | ||
| FR8812099A FR2636632B1 (en) | 1988-09-16 | 1988-09-16 | RADIOPHARMACEUTICAL PRODUCTS CONSTITUTED BY TC COMPLEXES, RE OR INCLUDING LETTERS WITH TETRAPHOSPHONATES AND THEIR PREPARATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1990002571A1 true WO1990002571A1 (en) | 1990-03-22 |
Family
ID=9370067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/FR1989/000473 WO1990002571A1 (en) | 1988-09-16 | 1989-09-15 | Radiopharmaceutical products consisting of tetraphosphonate complexes |
Country Status (2)
| Country | Link |
|---|---|
| FR (1) | FR2636632B1 (en) |
| WO (1) | WO1990002571A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0468634A1 (en) * | 1990-06-18 | 1992-01-29 | The Dow Chemical Company | The use of macrocyclic aminophosphonic acid complexes as imaging agents |
| EP0538402A1 (en) * | 1990-07-06 | 1993-04-28 | Mallinckrodt Medical, Inc. | Method of preparing a radioactive rhenium complex solution |
| WO1994026754A1 (en) * | 1993-05-06 | 1994-11-24 | The Dow Chemical Company | Bicyclopolyazamacrocyclophosphonic acids, their complexes and conjugates, for use as contrast agents, and processes for their preparation |
| WO1994026755A1 (en) * | 1993-05-06 | 1994-11-24 | The Dow Chemical Company | Bicyclopolyazamacrocyclophosphonic acid complexes, a process for their preparation, and their conjugates, for use as radiopharmaceuticals |
| EP1698357B1 (en) * | 2000-11-20 | 2019-06-26 | Universite De Geneve | Polyphosphonic acids and derivatives thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4032625A (en) * | 1973-06-11 | 1977-06-28 | Research Corporation | Bone-seeking technetium-99m complex |
| EP0002485A1 (en) * | 1977-12-15 | 1979-06-27 | Hoechst Aktiengesellschaft | Process for the preparation of marking compositions containing tin |
| US4187284A (en) * | 1976-12-16 | 1980-02-05 | Merck & Co., Inc. | Skeletal imaging kit utilizing triethylene tetramine hexa (methylene phosphonic acid) |
| US4560548A (en) * | 1984-04-10 | 1985-12-24 | The Dow Chemical Company | Bone seeking Tc-99m complexes of phosphonate derivatives of bis(aminoalkyl)piperazine |
| WO1987005030A1 (en) * | 1986-02-13 | 1987-08-27 | Celltech Limited | Conjugate compound |
-
1988
- 1988-09-16 FR FR8812099A patent/FR2636632B1/en not_active Expired - Fee Related
-
1989
- 1989-09-15 WO PCT/FR1989/000473 patent/WO1990002571A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4032625A (en) * | 1973-06-11 | 1977-06-28 | Research Corporation | Bone-seeking technetium-99m complex |
| US4187284A (en) * | 1976-12-16 | 1980-02-05 | Merck & Co., Inc. | Skeletal imaging kit utilizing triethylene tetramine hexa (methylene phosphonic acid) |
| EP0002485A1 (en) * | 1977-12-15 | 1979-06-27 | Hoechst Aktiengesellschaft | Process for the preparation of marking compositions containing tin |
| US4560548A (en) * | 1984-04-10 | 1985-12-24 | The Dow Chemical Company | Bone seeking Tc-99m complexes of phosphonate derivatives of bis(aminoalkyl)piperazine |
| WO1987005030A1 (en) * | 1986-02-13 | 1987-08-27 | Celltech Limited | Conjugate compound |
Non-Patent Citations (3)
| Title |
|---|
| Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science, Volume 33, No. 4, Partie 1, Avril 1984, Plenum Publishing Corporation, I.M. KABACHNIK et al.: "Synthesis and Acid-Base and Complex-Forming Properties of 1,4,7,10-Tetrakis-(Dihydroxyphosphorylmethyl)-1,4,7,10-Tetraazacyclododecane", pages 777-782 * |
| Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science, Volume 36, No. 2, Partie 2, Fevrier 1987, Plenum Publishing Corporation, S.A. PISAREVA et al.: "Synthesis and Complexing Properties of 1,5,8,12-Tetrakis(Dihydroxyphosphorylmethyl)-1,5,8,12-Tetraazacyclotetradecane, a Cyclopendant Phosphororganic Complexon", pages 372-376 * |
| CHEMICAL ABSTRACTS, Tenth Collective Index, Volumes 86-95, 1977-1981, American Chemical Society, (US), voir page 4904F* Colonne du Milieu: C10H18012P4, & Chemical Abstracts, Volume 90, No. 12, 19 Mars 1979, (Columbus, Ohio, US), voir page 224, resume 91154a* * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0468634A1 (en) * | 1990-06-18 | 1992-01-29 | The Dow Chemical Company | The use of macrocyclic aminophosphonic acid complexes as imaging agents |
| EP0538402A1 (en) * | 1990-07-06 | 1993-04-28 | Mallinckrodt Medical, Inc. | Method of preparing a radioactive rhenium complex solution |
| EP0538402A4 (en) * | 1990-07-06 | 1994-07-27 | Mallinckrodt Medical Inc | Method of preparing a radioactive rhenium complex solution |
| WO1994026754A1 (en) * | 1993-05-06 | 1994-11-24 | The Dow Chemical Company | Bicyclopolyazamacrocyclophosphonic acids, their complexes and conjugates, for use as contrast agents, and processes for their preparation |
| WO1994026755A1 (en) * | 1993-05-06 | 1994-11-24 | The Dow Chemical Company | Bicyclopolyazamacrocyclophosphonic acid complexes, a process for their preparation, and their conjugates, for use as radiopharmaceuticals |
| EP1698357B1 (en) * | 2000-11-20 | 2019-06-26 | Universite De Geneve | Polyphosphonic acids and derivatives thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2636632B1 (en) | 1996-02-02 |
| FR2636632A1 (en) | 1990-03-23 |
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