EP0527131A1 - Agents de chelation - Google Patents
Agents de chelationInfo
- Publication number
- EP0527131A1 EP0527131A1 EP91902213A EP91902213A EP0527131A1 EP 0527131 A1 EP0527131 A1 EP 0527131A1 EP 91902213 A EP91902213 A EP 91902213A EP 91902213 A EP91902213 A EP 91902213A EP 0527131 A1 EP0527131 A1 EP 0527131A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- groups
- formula
- compound
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 claims abstract description 43
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 239000002738 chelating agent Substances 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 96
- 229910052751 metal Inorganic materials 0.000 claims description 44
- 239000002184 metal Substances 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 38
- 239000013522 chelant Substances 0.000 claims description 34
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- -1 2,6-pyridindiyl Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 150000004697 chelate complex Chemical class 0.000 claims description 12
- 239000000032 diagnostic agent Substances 0.000 claims description 11
- 229940039227 diagnostic agent Drugs 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 238000001784 detoxification Methods 0.000 claims description 10
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 9
- 230000005298 paramagnetic effect Effects 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 229910001385 heavy metal Inorganic materials 0.000 claims description 8
- 238000001959 radiotherapy Methods 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 6
- 230000002285 radioactive effect Effects 0.000 claims description 6
- 238000002595 magnetic resonance imaging Methods 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 241000894007 species Species 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229910052692 Dysprosium Inorganic materials 0.000 claims description 3
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 238000002604 ultrasonography Methods 0.000 claims description 3
- 229910052689 Holmium Inorganic materials 0.000 claims description 2
- 229910052804 chromium Inorganic materials 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 229910052748 manganese Inorganic materials 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- 229910052693 Europium Inorganic materials 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000002708 enhancing effect Effects 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims 1
- 239000002872 contrast media Substances 0.000 abstract description 9
- 238000002059 diagnostic imaging Methods 0.000 abstract description 3
- 230000003439 radiotherapeutic effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 239000000047 product Substances 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 239000007787 solid Substances 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 229940123150 Chelating agent Drugs 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000007792 addition Methods 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 230000029936 alkylation Effects 0.000 description 9
- 238000005804 alkylation reaction Methods 0.000 description 9
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 5
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 239000011565 manganese chloride Substances 0.000 description 5
- 229960003330 pentetic acid Drugs 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- XUSNPFGLKGCWGN-UHFFFAOYSA-N 3-[4-(3-aminopropyl)piperazin-1-yl]propan-1-amine Chemical compound NCCCN1CCN(CCCN)CC1 XUSNPFGLKGCWGN-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000001588 bifunctional effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229960005069 calcium Drugs 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000002143 fast-atom bombardment mass spectrum Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229920000768 polyamine Polymers 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- QUTSYCOAZVHGGT-UHFFFAOYSA-N 2,6-bis(bromomethyl)pyridine Chemical compound BrCC1=CC=CC(CBr)=N1 QUTSYCOAZVHGGT-UHFFFAOYSA-N 0.000 description 3
- BEZVGIHGZPLGBL-UHFFFAOYSA-N 2,6-diacetylpyridine Chemical compound CC(=O)C1=CC=CC(C(C)=O)=N1 BEZVGIHGZPLGBL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 101000935117 Homo sapiens Voltage-dependent P/Q-type calcium channel subunit alpha-1A Proteins 0.000 description 3
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 3
- 208000036758 Postinfectious cerebellitis Diseases 0.000 description 3
- 102100025330 Voltage-dependent P/Q-type calcium channel subunit alpha-1A Human genes 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- PMWXGSWIOOVHEQ-UHFFFAOYSA-N pyridine-2,6-dicarbaldehyde Chemical compound O=CC1=CC=CC(C=O)=N1 PMWXGSWIOOVHEQ-UHFFFAOYSA-N 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- RCVAPWJFQRVQMF-UHFFFAOYSA-N 1,4,7,10,13-pentazabicyclo[11.2.2]heptadecane Chemical compound C1CN2CCN1CCNCCNCCNCC2 RCVAPWJFQRVQMF-UHFFFAOYSA-N 0.000 description 2
- VBNWSEVVMYMVLC-UHFFFAOYSA-N 1-(4-methylphenyl)sulfonylaziridine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1CC1 VBNWSEVVMYMVLC-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 2
- OQHNHHGLVQMIMI-UHFFFAOYSA-N 4,7,10-tris-(4-methylphenyl)sulfonyl-1,4,7,10,13-pentazabicyclo[11.2.2]heptadecane Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1CCN(S(=O)(=O)C=2C=CC(C)=CC=2)CCN(S(=O)(=O)C=2C=CC(C)=CC=2)CCN(CC2)CCN2CC1 OQHNHHGLVQMIMI-UHFFFAOYSA-N 0.000 description 2
- CCAOXFHSIMJBQQ-UHFFFAOYSA-N 4-methyl-n-[2-[4-[2-[(4-methylphenyl)sulfonylamino]ethyl]piperazin-1-yl]ethyl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NCCN1CCN(CCNS(=O)(=O)C=2C=CC(C)=CC=2)CC1 CCAOXFHSIMJBQQ-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229910003317 GdCl3 Inorganic materials 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000002616 MRI contrast agent Substances 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000008156 Ringer's lactate solution Substances 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- WWFMINHWJYHXHF-UHFFFAOYSA-N [6-(hydroxymethyl)pyridin-2-yl]methanol Chemical compound OCC1=CC=CC(CO)=N1 WWFMINHWJYHXHF-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000003957 anion exchange resin Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000012267 brine Substances 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
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 2
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 2
- 229940106681 chloroacetic acid Drugs 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MEANOSLIBWSCIT-UHFFFAOYSA-K gadolinium trichloride Chemical compound Cl[Gd](Cl)Cl MEANOSLIBWSCIT-UHFFFAOYSA-K 0.000 description 2
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(III) oxide Inorganic materials [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000005291 magnetic effect Effects 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- ROCPIINGAIULFR-UHFFFAOYSA-N n'-(pyridin-2-ylmethyl)-n-[2-(pyridin-2-ylmethylamino)ethyl]ethane-1,2-diamine Chemical compound C=1C=CC=NC=1CNCCNCCNCC1=CC=CC=N1 ROCPIINGAIULFR-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003182 parenteral nutrition solution Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/228—Host-guest complexes, clathrates, chelates
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Definitions
- the present invention relates to certain novel chelating agents, in particular polyamines, and to their uses, especially their medical uses.
- compositions as antidotes for poisonous heavy metal species and as diagnostic agents for the administration of metal species (e.g. ions or atoms) for diagnostic techniques such as X-ray, magnetic resonance imaging (MRI) or ultrasound imaging or scintigraphy.
- metal species e.g. ions or atoms
- diagnostic techniques such as X-ray, magnetic resonance imaging (MRI) or ultrasound imaging or scintigraphy.
- Polyamine chelating agents for example aminopoly- (carboxylic acid or carboxylic acid derivative)
- APCA chelating agents and their metal chelates
- EP-A-71564 describes
- paramagnetic metal chelates for which the chelatingagents are nitrilotriacetic acid (NTA),
- N,N,N',N'-ethylenediamine-tetraacetic acid EDTA
- N-hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid HEDTA
- DTPA N,N,N',N",N"- diethylenetriaminepentaacetic acid
- N-hydroxyethyl-iminodiacetic acid as being suitable as contrast agents for MRI, contrast being achieved by the effect of the magnetic field of the paramagnetic species (e.g. Gd(III)) with the chelating agents serving to reduce the toxicity and to assist administration of that paramagnetic species.
- the paramagnetic species e.g. Gd(III)
- Gd DTPA 1,4,7,10- tetraazacyclododecanetetraacetic acid
- each X independently represents an oxygen or sulphur atom or a group of formula NA, or
- E represents COH, NR 2 , O or S
- each A independently represents a hydrogen atom or a group (CR 2 R 3 ) p Y, (CR 2 R 3 ) n N[(CR 2 R 3 ) p Y] 2 or
- each Y independently represents a group COZ, SO 2 Z, POZ 2 ,
- each Z independently represents a group OR 2 or NR 2 R 2 ; each G is a 3 or 4 membered chain of carbon atoms and optionally a nitrogen, oxygen or sulphur atom; each J is a 2 or 3 membered chain of carbon atoms and optionally a nitrogen, oxygen or sulphur atom; each n is an integer of 2 to 4, preferably 2 or 3 or in a group (CR 2 R 3 ) n attached to a moiety R 1 which represents a hydrogen atom or a group R 4 n may also be zero or 1;
- n is an integer of 3 to 8 , preferably 3 to 6;
- p is an integer of 1 to 3, preferably 1;
- each R 1 represents a hydrogen atom or a group R 4 or together both groups R 1 represent a carbon-carbon bond; each R 2 independently represents a hydrogen atom or a C 1-8 alkyl group optionally mono- or poly-substituted by hydroxyl or C 1-8 alkoxy groups or NR 2 R 2 may together represent a nitrogen-attached 5 to 7 membered saturated heterocyclic ring optionally containing as a further ring heteroatom a nitrogen, oxygen or sulphur atom and optionally substituted by a group R 4 ;
- each R 3 independently represents a hydrogen atom or a C 1-8 alkyl or C 1-8 alkoxy group optionally mono or poly substituted by hydroxy or C 1-8 alkoxy groups;
- each R 4 independently represents a hydrogen atom, a halogen atom, a hydroxyl group, an optionally mono- or poly-hydroxylated C 1-8 alkyl, C 1-8 alkoxy, (C 1-8 alkoxy)-C 1-8 alkyl or poly(C 1-8 alkoxy)-C 1-8 alkyl group, a sulphonate group or a group (CR 2 R 3 ) Y or two groups R 4 on the same ring represent a (CR 2 R 3 ) n-1 [X(CR 2 R 3 ) n ] m-1 (CR 2 R 3 ) n-1 group in which case the said ring may be saturated; with the provisos that at least 2 Y groups, preferably at least 3, are present, that where both groups R 1 together form a bond, m is 4 or 5, all n are 2, one X is
- heterocyclic group or both R groups together represent a bond and two (CR 2 R 3 ) p Y groups together represent a
- R 1 groups represent a bond
- m is 6 or greater and two X groups separated by at least two other X groups are oxygen or sulphur atoms, and preferably that where m is 3 or 4, all n are 2, one X is
- R 2 , R 3 or R 4 is other than hydrogen or a chelate complex or salt thereof.
- alkyl In the compounds of the invention, alkyl or
- alkylene moieties in groups R 1 to R 4 may be straight chained or branched and
- substituents may themselves optionally be substituted by hydroxyl or alkoxy groups, this may be monosubstitution or polysubstitution and, in the case of polysubstitution, alkoxy or hydroxyl
- substituents may be carried by alkoxy substituents.
- the compounds of the invention incorporate one or more hydrophilic R 1 to R 4 groups, these are preferably straight-chained or branched moieties having a carbon atom content of from 1 to 8, especially preferably 1 to 6, carbon atoms.
- the hydrophilic groups may be alkoxy, polyalkoxy,
- hydroxylated alkoxyalkyl polyhydroxylated alkoxyalkyl, hydroxylated polyalkoxyalkyl, or polyhydroxylated polyalkoxyalkyl groups. More preferably however they will be monohydroxyalkyl or polyhydroxyalkyl groups.
- hydrophilic groups serve to increase the hydrophilic groups
- the compounds of formula I should contain at least 1, conveniently from 1 to 4, and preferably 1, 2 or 3 such hydrophilic groups.
- hydrophilic groups the compounds of the invention may thus include for example hydroxymethyl,
- Particularly preferred compounds of formula I according to the invention include those of monocyclic structure containing at least 6 ring heteroatoms, those of fused bicyclic structure containing at least two ring heteroatoms in the smaller ring, and those of fused tricyclic or higher polycyclic structure.
- the aromatic groups comprised by X groups preferably are pyridine, pyrazine, pyrrole, furan, phenol, pyrimidine or
- thiophene rings especially pyridine rings.
- E is COH, e.g. where X comprises a phenol group, it is especially preferred that an electron withdrawing R 4 substituent (e.g. a lower alkyl or halogen such as chlorine or methyl) should be present on the ring, preferably at the para position to the hydroxyl group.
- R 4 substituent e.g. a lower alkyl or halogen such as chlorine or methyl
- adjacent X groups preferably do not both comprise such aromatic groups.
- adjacent X groups preferably do not both comprise such aromatic groups.
- piperazine or 1,4-diazacycloheptane rings, especially piperazin-1,4-diyl groups.
- one, two or three X groups should comprise such aromatic groups, the remaining X groups, or all but one remaining X group being
- groups X comprising no ionizing group Y should be non-adjacent particularly that they should adopt opposed positions in macrocyclic chelants, e.g. as the 1st and 5th X groups in an 8 X ring.
- Particularly preferred compounds of formula I include those of formulae lb and Ic
- v 0,1,2,3 or 4 and X 2 is O or S).
- W is CHR4 , NR 4 , O or S, where q is zero W preferably being CHR 4 .
- CONCHR 4 CHR 4 W(CHR 4 ) CHR 4 , CONHR 2" or CONR 2" 2 (where R 2" is an alkyl or mono or poly hydroxyalkyl group, for example a C 1 -6 alkyl group optionally carrying 1, 2, 3 or 4 hydroxyl groups). Particularly preferably, in the case where R 1 are not bonds terminal X groups will comprise an aromatic heterocyclic group.
- the compounds of formula I can conveniently form salts or chelates in which Y represents -COOM (wherein M + is a monovalent cation or a fraction of a polyvalent cation, for example an ammonium or substituted ammonium ion or a metal ion, for example an alkali metal or alkaline earth metal ion).
- M + is a cation deriving from an organic base, for example meglumine or lysine.
- M + is a cation deriving from an organic base, for example meglumine or lysine.
- the number of the ion-forming groups Y in the compounds of formula I be chosen to egual the valency of the metal species to be chelated by the compound formula I.
- the compound of formula I preferably contains three or six ion-forming Y groups, for example -COOH (or -COOM).
- the metal chelate will be formed as a neutral species, a form preferred since the osmolalities in concentrated solutions of such compounds are low and since their toxicities relative to their ionic analogues are significantly reduced.
- each R 2 represents a hydrogen atom or a mono- or poly-hydroxylated alkyl group
- Y represents a group of formula COZ
- Z represents a hydroxyl group or a group NHR 2 ) and metal chelates and salt thereof.
- Especially preferred compounds according to the invention include those of the following formulae Im to
- R 2 " is hydrogen or methyl
- R 6 is a carboxymethyl group or derivative thereof, e.g. CH 2 COOH
- each R 4" may also represent a C 1-4 hydroxyalkyl group) and the metal chelates and the salts thereof.
- Particularly preferred compounds according to the invention include those of formulae Ij to lo wherein R 6 is CH 2 COOH and the chelates, e.g. with Gd 3+ , and salts thereof.
- the invention also provides a process for the preparation of the compounds of the invention, said process comprising one or more of the following steps:
- R 1' to R 3' are as defined for R 1 to R 3 or are protected R 1 to R 3 groups, and X' is a group X or a protected group X with the proviso that at least one X ' group is of formula NH or (CR 2' R 3 ' ) p NH 2 ) with a compound of formula III
- LV-(CR 2' R 3 ' ) p -Y' (III) (where Y' is a group Y or a protected group Y, R 2' and R 3' are as hereinbefore defined and Lv is a leaving group for example a halogen atom, e.g. bromine or chlorine or a tosylate group) and if necessary
- the compounds of formula II are known from the literature or may be prepared in a number of ways using techniques known from the literature or analogous to literature described techniques. Thus for example such compounds may be prepared by condensing mono or
- R 2 , R 3 , and R 4' are as defined for R 2 to R 4 or are protected R 2 to R 4 groups and R 12 is hydrogen, an amine protecting group or a group (CR 2' R 3' ) n-1 COR 3' ) with a linking molecule of formula V
- R 2' and R 3' are as hereinbefore defined, mid-chain X" groups, if any are groups X' and end of chain X" groups are oxygen, sulphur or ring nitrogen atoms or, preferably, NH groups) followed if necessary by removal of any protecting groups and if necessary by reduction.
- the compounds of formula II may also be prepared by activating starting compounds of formula V, e.g. by tosylation, and condensing the product with a mono or bifunctional heterocyclic compound of formulae VI or VII
- R 13 is hydrogen, an amine protecting group or a group (CR 2' R 3, ) Lv)
- linear or cyclic compounds of formula II can be prepared using the following reaction schemes.
- group may be prepared by condensing a linear compound having active groups at each end with a compound of formula
- the active linear compound of formula XII may of course be prepared by other routes, e.g.
- macrocyclic chelants i.e. compounds wherein two R 4 groups on a cyclic X group together represent a group (CR 2 R 3 ) n-1 [X(CR 2 R 3 ) n ] m-1 (CR 2 R 3 ) n-1 - can be prepared for example by a condensation equivalent to those of the schemes above using a tetrafunctional precursor for the cyclic X group and bifunctional co-reagents. It may be desirable to utilize aromatic tetrafunctional precursors and subsequently to reduce the product, e.g. by high pressure catalytic hydrogenation.
- compounds of formula II may be prepared by the following scheme:
- step (a) To introduce a (CR 2 R 3 ) Y group onto a compound of formula II using the precedure of step (a) may be effected in an aqueous, preferably basic, medium, for example by using a halocarboxylic acid Hal(CR 2' R 3' ) p -
- Amide derivatives of formula I may be produced from the oligo acids by methods analogous to those of
- EP-A-250358 or of EP-A-299795 Furthermore hydrophilic substituents on the skeleton of the linear or cyclic chelants of formula I may be introduced by methods analogous to those of EP-A-299795.
- Chelants of formula I may be used as the basis for bifunctional chelants or for polychelant compounds, that is compounds containing several independant chelant groups, by substituting for one Y or R 1 to R 4 group a bond or linkage to a macromolecule or polymer, e.g. a tissue specific biomolecule or a backbone polymer such as polylysine or polyethyleneimine which may carry several chelant groups and may itself be attached to a macromolecule to produce a bifunctional-polychelant.
- a macromolecule or polymer e.g. a tissue specific biomolecule or a backbone polymer such as polylysine or polyethyleneimine which may carry several chelant groups and may itself be attached to a macromolecule to produce a bifunctional-polychelant.
- Such macromolecular derivatives of the compounds of formula I and the metal chelates and salts thereof form a further aspect of the present invention.
- macromolecule or backbone polymer may be effected by any of the conventional methods such as the carbodiimide method, the mixed anhydride procedure of Krejcarek et al. (see Biochemical and Biophysical Research
- Salt and chelate formation may be performed in a conventional manner.
- the chelating agents of the formula I are particularly suitable for use in detoxification or in the formation of metal chelates, chelates which may be used for example in or as contrast agents for in vivo or in vitro magnetic resonance (MR), X-ray or ultrasound diagnostics (e.g. MR imaging and MR spectroscopy), or scintigraphy or in or as therapeutic agents for
- Salts or chelate complexes of the compounds of the invention containing a heavy metal atom or ion are particularly useful in diagnostic imaging or therapy. Especially preferred are salts or complexes with metals of atomic numbers 20-32,42-44,49 and 57 to 83,
- the chelated metal species is especially Gd, Dy and Yb.
- the chelated metal species is especially Gd, Dy and Yb.
- the metal conveniently being a transition metal or a lanthanide, preferably having an atomic number of 21-29, 42, 44 or 57-71.
- Gd, Dy, Ho, Cr, Mn or Fe are especially preferred and Gd 3+ , Mn 2+ and Dy 3+ are particularly preferred.
- Chelates of ions of these metals specifically listed above with chelants of formula I (defined as above with the exclusion of the second proviso) or their salts with physiologically tolerable counterions are particularly useful for the diagnostic imaging procedures mentioned herein and they and their use are deemed to fall within the scope of the invention and references to chelates of compounds of formula I herein are consequently to be taken to include such chelates.
- the paramagnetic metal species is conveniently non-radioactive as
- the chelated metal species is preferably a heavy metal species, for example a non-radioactive metal with an atomic number greater than 37, preferably greater than 50, e.g. Dy 3+ .
- the chelated metal species For use in scintigraphy and radiotherapy, the chelated metal species must of course be radioactive and any conventional complexable radioactive metal isotope, such as 99mTc or 111 In for example, may be used.
- the chelating agent may be in the form of a metal chelate with for example 153 Sm, 67 Cu or 90 Y.
- the chelating agent For use in detoxification of heavy metals, the chelating agent must be in weak complex or salt form with a physiologically acceptable counterion, e.g.
- sodium, calcium, ammonium, zinc or meglumine e.g. as the sodium salt of the chelate of the compound of formula I with zinc or calcium.
- the metal chelate carries an overall charge, such as is the case with the prior art Gd DTPA, it will conveniently be used in the form of a salt with a physiologically acceptable counterion, for example an ammonium, substituted ammonium, alkali metal or alkaline earth metal (e.g. calcium) cation or an anion deriving from an inorganic or organic acid.
- a physiologically acceptable counterion for example an ammonium, substituted ammonium, alkali metal or alkaline earth metal (e.g. calcium) cation or an anion deriving from an inorganic or organic acid.
- meglumine salts are particularly preferred.
- the present invention provides a diagnostic or therapeutic composition
- a metal chelate whereof the chelating entity is the residue of a compound of formula I according to the present invention, together with at least one pharmaceutical or veterinary carrier or excipient, or adapted for formulation therewith or for inclusion in a pharmaceutical formulation for human or veterinary use.
- the present invention provides a detoxification agent comprising a chelating agent according to the invention in the form of a weak complex or salt with a physiologically acceptable counterion, together with at least one pharmaceutical or veterinary carrier or excipient, or adapted for
- the diagnostic and therapeutic agents of the present invention may be formulated with conventional pharmaceutical or veterinary formulation aids, for example stablizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, etc. and may be in a form suitable for parenteral or enteral
- compositions of the present invention may be in conventional
- acceptable carrier media for example water for
- the compounds according to the invention may therefore be formulated for administration using
- Suitable additives include, for example, physiologically
- biocompatible buffers as for example, tromethamine hydrochloride
- additions e.g., 0.01 to 10 mole
- chelants such as, for example,. DTPA,
- DTPA-bisamide or non-complexed chelants of formula I or calcium chelate complexes (as for example calcium DTPA, CaNaDTPA-bisamide, calcium salts or chelates of chelants of formula I), or, optionally, additions (e.g., 1 to 50 mole percent) of calcium of sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate combined with metal chelate complexes of chelants formula I and the like).
- a small amount of soluble chelate may be mixed with one or more of the inactive ingredients traditionally present in oral solutions and/or
- parenterally administrable forms e.g., intravenous solutions
- Suitable vehicles include aqueous vehicles customarily used for administering parenteral solutions such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium
- solutions can contain preservatives, antimicrobial agents, buffers and antioxidants conventionally used for parenteral solutions, excipients and other additives which are compatible with the chelates and which will not interfere with the manufacture, storage or use of products.
- the diagnostic or therapeutic agent comprises a chelate or salt of a toxic metal species, e.g. a heavy metal ion
- a chelate or salt of a toxic metal species e.g. a heavy metal ion
- the diagnostic agent of the present invention if in
- solution, suspension or dispersion form will generally contain the metal chelate at concentration in the range 1 micromole to 1.5 mole per litre, preferably 0.1 to 700mM.
- the diagnostic agent may however be supplied in a more concentrated form for dilution prior to
- the diagnostic agent of the invention may conveniently be administered in amounts of from 10 -3 to 3 mmol of the metal species per kilogram of body weight, e.g. about 1 mmol Dy/kg bodyweight.
- the dose of the contrast agent should generally be higher and for scintigraphic examination the dose should generally be lower than for MR examination.
- conventional dosages may be used for radiotherapy and detoxification.
- the present invention provides a method of generating enhanced images of the human or non-human animal body, which method comprises administering to said body a diagnostic agent according to the present invention and generating an X-ray, MR, ultrasound or scintigraphic image of at least a part said body.
- the present invention provides a method of radiotherapy practised on the human or non-human animal body, which method comprises
- the present invention provides a method of heavy metal detoxification
- a chelating agent according to the invention in the form of a weak complex or salt with a physiologically acceptable counterion.
- the present invention also provides the use of the compounds, especially the metal chelates, according to the
- the present invention provides a process for the preparation of the metal chelates of the invention which process comprises admixing in a solvent a compound of formula I or a salt (e.g. the sodium salt) or chelate thereof together with an at least sparingly soluble compound of said metal, for example a chloride, oxide, acetate or carbonate.
- a solvent e.g. the sodium salt
- an at least sparingly soluble compound of said metal for example a chloride, oxide, acetate or carbonate.
- the present invention provides a process for the preparation of the diagnostic or therapeutic agent of the present invention
- the present invention provides a process for the preparation of the detoxification agent of the invention, which comprises admixing a chelating agent according to the invention in the form of a weak complex or salt with a
- physiologically acceptable counterion together with at least one pharmaceutical or veterinary carrier or excipient.
- ethanol/water (1/1) is placed in a 100 mL three neck round-bottom flask equipped with two addition funnels, pH electrode, thermometer, and stir bar.
- NaOH 199 mg, 4.98 mmol
- BrCH 2 CO 2 H 346 mg, 2.49 mmol
- the solution of NaOH is added to the amine solution to bring the pH to 10.5.
- the temperature is raised to 50°C and the
- Chloroacetic acid (24 g; 254 mmol) in water (500 ml) was adjusted to pH 7 with NaOH solution. This was added dropwise to a solution of [12]N 4 (py) (15.00 g; 727 mmol) in water maintained at a temperature of 95°C. During the addition, the pH is maintained at pH 9-10 by the addition of 1N NaOH solution.
- reaction mixture was adjusted to pH 3 using 1N HCl solution and concentrated to a solid.
- N,N'-Bis(N-tosylaminoethyl)piperazine (4.0 g, 8.7 mmol) was dissolved in 200 ml of DMF, and Cs CO (6.0 g, 18.4 mmol) was added. The mixture was stirred under a nitrogen atmosphere at 110°C for 2 hours before
- N,N-bis(tosyloxyethyl) amine (4.9 g, 8.6 mmol - prepared as described by Guerbet in EP-A-287465) in 80 ml of DMF was added dropwise over 0.5 hour. Stirring at 110°C was maintained for an additional 3 hours. The reaction mixture was evaporated to dryness. The resulting solid was stirred in CH 2 Cl 2 overnight. Undissolved material was filtered, and the solution was evaporated to
- HBr in acetic acid (32% w/w, 82 ml) was added to a mixture of phenol (4.3 g, 46 mmol) and 4,7,10- tris(tosyl)-1,4,7,10,13-pentaazabicyclo[11.2.2]heptadecane (2.06 g, 3 mmol).
- the solution was stirred at 70°C for 24 hours. The temperature was raised to 85°C, and stirring was continued for 5.5 hours. The solution was allowed to cool to ambient temperature.
- Precipitated solid was collected and triturated with ether and cold ethanol. The solid was then dissolved in water and passed down a Dowex AGI-8X column. Water was removed. Drying of the solid overnight yielded 0.32 g
- N, N''-bis(pyrid-2-yl- methyl) diethylenetriamine (23.6 g, 82.6 mmol) and diisopropylethylamine (53.4 g, 0.4 mol) in 1.2 L of methylene chloride at ambient temperature was added dropwise t-butylbromoacetate (50 g, 0.2 mol) in 300 mL of methylene chloride. After being stirred for 24 hours, the solution was evaporated to dryness and placed under vacuum for 2 hours to remove excess
- step (b) The tris(t-butylcarboxymethyl)ester (24.89g, 0.1 mol) of step (b) was dissolved in a solution of 600 mL of methylene chloride containing 380 mL of trifluoroacetic acid. The solution was stirred for 48 hours, evaporated under reduced pressure and diluted with 50 mL of water. This solution was applied to 200 mL of AG50-X8 (H + form, 100-200 mesh) and after washing with water until
- the product was eluted with 1N NH 4 OH. After removal of NH 4 OH solution, the product was taken up in 24 mL of water, and the solution was adjusted to pH 10 and then applied to AG1-X8 (acetate, 100-200 mesh). The column was washed with three bed volumes of water and the product eluted with 2 N HOAc to give 12.0 g (69%) of the title product after several lyophilizations.
- the title compound is prepared by reaction of 2,6- diformyl-pyridine with 1,4-di(2-aminoethyl) piperazine by the method of scheme (G), followed by alkylation with bromoacetic acid.
- the title compound is prepared by reaction of 2,6- diacetyl-pyridine with 1,4-di(2-aminoethyl)pipperazine by the method of scheme (G), followed by alkylation with bromoacetic acid.
- the title compound is prepared by reaction of 2,6- diformyl-pyridine with 1,4-di(3-aminopropyl)piperazine by the method of scheme (G), followed by alkylation with bromoacetic acid.
- the title compound is prepared by reaction of 2,6- diacetyl-pyridine with 1,4-di(3-aminopropyl)piperazine by the method of scheme (G), followed by alkylation with bromoacetic acid.
- the tetraimine:bisimine/bisimidazolidine (3.00 g, 7.42 mmol) was added to a suspension of sodium borohydride (1.17 g, 31 mmol) in 100 mL of ethanol. The mixture was stirred for 1 hour at ambient temperature, refluxed for 0.5 hours, and then stirred overnight at ambient
- Example 1 Example 1
- 5 mL of a 100 mM aqueous solution of GdCl 3 are mixed thoroughly and the pH is adjusted to 6.9 with 1N NaOH to yield the title product.
- T 1 and T 2 relaxivities of the chelate, in mM -1 s -1 measured in water at 10MHz and 37 °C were respectively 6.99 and 6.23.
- Example 20 The title compound is prepared analogously to that of Example 16 by reaction of the chelant of Example 2 with MnCl 2 .
- Example 20 The title compound is prepared analogously to that of Example 16 by reaction of the chelant of Example 2 with MnCl 2 .
- N,N"-Bis(pyrid-2-yl-methyl)diethylenetriamine-N,N'N"- triacetic acid (2,8719 g, 6.25 mmol) (the compound of Example 6) and gadolinium oxide (1.1328 g, 3.125 mmol) were combined in 15 mL of water and heated at 95°C for 4 hours to provide a solution of the desired complex.
- the title compound is prepared analogously to that of Example 16 by reaction of the chelant of Example 6 with CaCl 2 .
- composition comprising GdBis(py) DTTA and CaNa
- Example 23 The compounds of Examples 20 and 21 are admixed in a 95:5 (by weight) ratio and dispersed in water for injections to a Gd content of 400 mM.
- Example 23 The compounds of Examples 20 and 21 are admixed in a 95:5 (by weight) ratio and dispersed in water for injections to a Gd content of 400 mM.
- the title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 7 with GdCl 3 .
- the title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 8 with MnCl 2 .
- the title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 9 with MnCl 2 .
- Example 27 The title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 10 with MnCl 2 .
- Example 27 The title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 10 with MnCl 2 .
- the title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 11 with MnCl 2 .
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Abstract
L'invention se rapporte à de nouveaux agents de chélation utilisables dans la préparation d'agents de contraste pour des techniques de formation d'images diagnostiques ou dans la préparation de compositions radiothérapeutiques ou de détoxification.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB909001245A GB9001245D0 (en) | 1990-01-19 | 1990-01-19 | Compounds |
GB9001245 | 1990-01-19 |
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EP0527131A1 true EP0527131A1 (fr) | 1993-02-17 |
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EP91902213A Withdrawn EP0527131A1 (fr) | 1990-01-19 | 1991-01-18 | Agents de chelation |
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EP (1) | EP0527131A1 (fr) |
JP (1) | JPH05506426A (fr) |
AU (1) | AU7060291A (fr) |
CA (1) | CA2074171A1 (fr) |
FI (1) | FI923286A0 (fr) |
GB (1) | GB9001245D0 (fr) |
HU (1) | HUT61306A (fr) |
IE (1) | IE910189A1 (fr) |
NO (1) | NO922849L (fr) |
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US5334371A (en) * | 1988-07-20 | 1994-08-02 | Schering Aktiengesellschaft | Marcocyclic polyaza bicyclo compounds containing 5 or 6 membered rings, and method for MRI |
FR2644785B1 (fr) * | 1989-03-24 | 1991-07-05 | Guerbet Sa | Nouveaux ligands macrocycliques azotes, procede de preparation, complexes metalliques formes par ces ligands et composition de diagnostic les contenant |
US5367080A (en) * | 1990-11-08 | 1994-11-22 | Sterling Winthrop Inc. | Complexing agents and targeting radioactive immunoreagents useful in therapeutic and diagnostic imaging compositions and methods |
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-
1990
- 1990-01-19 GB GB909001245A patent/GB9001245D0/en active Pending
-
1991
- 1991-01-18 JP JP91502458A patent/JPH05506426A/ja active Pending
- 1991-01-18 CA CA002074171A patent/CA2074171A1/fr not_active Abandoned
- 1991-01-18 WO PCT/EP1991/000126 patent/WO1991010645A2/fr not_active Application Discontinuation
- 1991-01-18 HU HU922347A patent/HUT61306A/hu unknown
- 1991-01-18 EP EP91902213A patent/EP0527131A1/fr not_active Withdrawn
- 1991-01-18 AU AU70602/91A patent/AU7060291A/en not_active Abandoned
- 1991-01-21 IE IE018991A patent/IE910189A1/en unknown
-
1992
- 1992-07-17 NO NO92922849A patent/NO922849L/no unknown
- 1992-07-17 FI FI923286A patent/FI923286A0/fi not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9110645A2 * |
Also Published As
Publication number | Publication date |
---|---|
HUT61306A (en) | 1992-12-28 |
GB9001245D0 (en) | 1990-03-21 |
JPH05506426A (ja) | 1993-09-22 |
WO1991010645A2 (fr) | 1991-07-25 |
WO1991010645A3 (fr) | 1991-12-26 |
IE910189A1 (en) | 1991-07-31 |
AU7060291A (en) | 1991-08-05 |
NO922849D0 (no) | 1992-07-17 |
FI923286A (fi) | 1992-07-17 |
CA2074171A1 (fr) | 1991-07-20 |
FI923286A0 (fi) | 1992-07-17 |
HU9202347D0 (en) | 1992-10-28 |
NO922849L (no) | 1992-09-04 |
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