EP0440606A1 - Macrocyclic chelating agents and chelates thereof - Google Patents
Macrocyclic chelating agents and chelates thereofInfo
- Publication number
- EP0440606A1 EP0440606A1 EP89900817A EP89900817A EP0440606A1 EP 0440606 A1 EP0440606 A1 EP 0440606A1 EP 89900817 A EP89900817 A EP 89900817A EP 89900817 A EP89900817 A EP 89900817A EP 0440606 A1 EP0440606 A1 EP 0440606A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tetraaza
- carboxymethyl
- benzyloxy
- hydroxy
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002738 chelating agent Substances 0.000 title claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 16
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 14
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical class C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 50
- 150000001875 compounds Chemical class 0.000 claims description 41
- -1 hydroxy, carboxy, carbamoyl Chemical group 0.000 claims description 34
- 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 claims description 28
- 238000000034 method Methods 0.000 claims description 24
- 229940080818 propionamide Drugs 0.000 claims description 23
- 150000002500 ions Chemical class 0.000 claims description 17
- 229910021645 metal ion Inorganic materials 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 16
- ALRHLSYJTWAHJZ-UHFFFAOYSA-N 3-hydroxypropionic acid Chemical compound OCCC(O)=O ALRHLSYJTWAHJZ-UHFFFAOYSA-N 0.000 claims description 14
- OZGUGVRKYBSDBN-UHFFFAOYSA-N 3-phenylmethoxypropanoic acid Chemical compound OC(=O)CCOCC1=CC=CC=C1 OZGUGVRKYBSDBN-UHFFFAOYSA-N 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 5
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 5
- 239000013522 chelant Substances 0.000 claims description 5
- LQVXSNNAFNGRAH-QHCPKHFHSA-N BMS-754807 Chemical compound C([C@@]1(C)C(=O)NC=2C=NC(F)=CC=2)CCN1C(=NN1C=CC=C11)N=C1NC(=NN1)C=C1C1CC1 LQVXSNNAFNGRAH-QHCPKHFHSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 229910052738 indium Inorganic materials 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 238000009206 nuclear medicine Methods 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 229910052692 Dysprosium Inorganic materials 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229910052748 manganese Inorganic materials 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 238000002405 diagnostic procedure Methods 0.000 claims 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims 1
- 229930002839 ionone Natural products 0.000 claims 1
- 150000002499 ionone derivatives Chemical class 0.000 claims 1
- 229910044991 metal oxide Inorganic materials 0.000 claims 1
- 150000004706 metal oxides Chemical class 0.000 claims 1
- 150000003354 serine derivatives Chemical class 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000032 diagnostic agent Substances 0.000 abstract 1
- 229940039227 diagnostic agent Drugs 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 235000013350 formula milk Nutrition 0.000 description 22
- 229940123150 Chelating agent Drugs 0.000 description 17
- 238000000921 elemental analysis Methods 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 230000008569 process Effects 0.000 description 11
- 239000002872 contrast media Substances 0.000 description 9
- 238000007792 addition Methods 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000003745 diagnosis Methods 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 229920002521 macromolecule Polymers 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- UTIXQHCSWSIAEC-UHFFFAOYSA-M sodium;2-chloro-3-phenylmethoxypropanoate Chemical compound [Na+].[O-]C(=O)C(Cl)COCC1=CC=CC=C1 UTIXQHCSWSIAEC-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- UKXGJLIJNUBRKM-UHFFFAOYSA-N 2-chloro-3-phenylmethoxypropanoyl chloride Chemical compound ClC(=O)C(Cl)COCC1=CC=CC=C1 UKXGJLIJNUBRKM-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 230000005298 paramagnetic effect Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- NRBAANSGRYYGBW-UHFFFAOYSA-N 3-phenylmethoxy-2-(1,4,7,10-tetrazacyclododec-1-yl)propanoic acid Chemical compound C1CNCCNCCNCCN1C(C(=O)O)COCC1=CC=CC=C1 NRBAANSGRYYGBW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000040710 Chela Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910052769 Ytterbium Inorganic materials 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229910052804 chromium Inorganic materials 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229910052733 gallium Inorganic materials 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000005191 hydroxyalkylamino group Chemical group 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052746 lanthanum Inorganic materials 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 230000001926 lymphatic effect Effects 0.000 description 2
- 230000005291 magnetic effect Effects 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229910052713 technetium Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229940073585 tromethamine hydrochloride Drugs 0.000 description 2
- CUGDYSSBTWBKII-LXGUWJNJSA-N (2r,3r,4r,5s)-6-(dimethylamino)hexane-1,2,3,4,5-pentol Chemical compound CN(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO CUGDYSSBTWBKII-LXGUWJNJSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- ILROLYQPRYHHFG-UHFFFAOYSA-N 1-$l^{1}-oxidanylprop-2-en-1-one Chemical group [O]C(=O)C=C ILROLYQPRYHHFG-UHFFFAOYSA-N 0.000 description 1
- QEYBMJSQGBIRHS-UHFFFAOYSA-N 2-chloro-3-phenylmethoxypropanoic acid Chemical compound OC(=O)C(Cl)COCC1=CC=CC=C1 QEYBMJSQGBIRHS-UHFFFAOYSA-N 0.000 description 1
- XQGWRBMQUDXMRH-UHFFFAOYSA-N 3-hydroxy-2-methylpropanamide Chemical compound OCC(C)C(N)=O XQGWRBMQUDXMRH-UHFFFAOYSA-N 0.000 description 1
- OQGHTRNRMYIWBJ-UHFFFAOYSA-N 4-hydroxy-2-methylbutanamide Chemical compound NC(=O)C(C)CCO OQGHTRNRMYIWBJ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 235000003197 Byrsonima crassifolia Nutrition 0.000 description 1
- 240000001546 Byrsonima crassifolia Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 1
- 238000004435 EPR spectroscopy Methods 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
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- 102000008100 Human Serum Albumin Human genes 0.000 description 1
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- 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 1
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- DDTBPAQBQHZRDW-UHFFFAOYSA-N cyclododecane Chemical compound C1CCCCCCCCCCC1 DDTBPAQBQHZRDW-UHFFFAOYSA-N 0.000 description 1
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
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- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
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- 150000004676 glycans Polymers 0.000 description 1
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- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 238000002075 inversion recovery Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000002310 reflectometry Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Chemical class 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000001173 tumoral effect Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- 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
Definitions
- the present invention relates to novel macrocyclic chela ⁇ ting agents deriving from 1, , 7,10-tetraazacyclododecane of general formula I ⁇
- A is a group of formula
- R is H or a C -C straight or branched alkyl group, or a benzyl group which can be mono- or poly-substituted on the aromatic ring by halogen, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, sulphamoyl, lower alkyl, lower hydroxyalkyl, amino, acylamino, acyl, hydroxyacyl groups, or a group of formula H(OCH CH ) -,
- X is a O-R group in which R.. is H or a C -C_ alkyl, 1 1 5 hydroxyalkyl, alkoxyalkyl, alkoxyhydroxyalkyl group, or a polyoxaalkyl group having 1 to 15 oxygen atoms and 3 to 45 carbon atoms, or X is a -NR R group in which R and R , which can be the same or different, are C -C 3 1 6 alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl groups having up to 5 hydroxy groups and
- B , B and B which can be the same or different, have the same meaning as A or they are H or a group of formula
- R is H or a C -C straight or branched alkyl group
- Y is a O-R group in which R is H or a C -C alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyhydroxyalkyl group, or a polyoxaalkyl group having 1 to 15 oxygen atoms and 3 to 45 carbon atoms, or Y is a-NR R group in which R
- R which can be the same or different, are H or
- the present invention also relates to the preparation of compounds of general formula I and of the complex salts thereof, to their uses and, when indicated, to the pharma- ceutical and diagnostic compositions thereof.
- the chelating compounds of the present invention and the complex salts thereof can have a wide range of applica ⁇ tions.
- No limiting examples of use of said chelating agents are jthe recovery, separation, selective extraction of metal ions even at very low concentrations, their therapeutical use as detoxifying agents in cases of inadvertent bodily incorporation of metals or radioiso- topes, their use as ion carriers, or the other ones appa ⁇ rent to those skilled in the art.
- the chelat- ing agents may be used directly or often they have been bonded covalently or non-covalently to macromolecules or insoluble surfaces or have been otherwise incorporated into structures that can carry them to specific sites.
- the complex salts of the chelating agents of formula I with the metal ions of the elements with atomic numbers of 20 to 31, 39, 42, 43, 44, 49 or 57 to 83 and, optionally, salified by physiologically biocompatible ions of organic or inorganic acids or organic or inorganic bases or aminoacids are surprisingly suitable for use as contrast agents in medical diagnosis in nuclear medicine and in N.M.R., E.S.R., X-ray and/or ultrasonic diagnosis.
- Said derivatives for the purpose of optimal diagnostic use, can also be bound or incorporated covalently or non-covalently into biomolecules, .macromolecules or mole- cular aggregates characterized in that they can selective- ly concentrate in the organ or in the tissue under examination.
- radioisotopes as internal tracers in the organism should be mentioned.
- One of the biggest problems connected with the use of radioisotopes is their selectivity of distribution, while another important aspect is their excretion in an accepta- ble time.
- Another imaging technique concerns with the use of ultrasounds to measure the difference in the reflections at the interfaces between tissues of different density.
- the administration of a suitable amount of a dense non-radioactive element or metal ion can give such a dif ⁇ ference in reflectivity that can emphasize even small otherwise non detectable lesions.
- a third diagnostic technique uses nuclear magnetic reso ⁇ nance to create internal images of the human body.
- the development of contrast agents is of particular importance for the following reasons: a) to improve the specificity of the diagnosis, b) to identify at an earlier stage small lesions, c) to more precisely define the extension of a tumoral mass, d) to improve the signal to noise ratio and to shorten the time of acquisition of the images, allowing also better use of the instruments, e) to increase the contrast between those contiguous areas (for instance abdominal or pelvic) where it is parti- cularly difficult to obtain well defined images, f) to obtain good informations on blood flow and on tissue perfusion.
- contrast media containing paramagnetic complex salts of lanthanides and transition metals have already been claimed for instance in EP 71564 and in US-Pat. 4,639,365, and in patent appli ⁇ cations DE 3401052, EP-A 135125, EP-A 130934, DE 3324236, EP-A 124766, EP-A 165728, WO 87/02893, EP-A 230893.
- contrast agents for N.M.R. present some problems as far as regards their capa ⁇ city of influencing the relaxation time of the atomic nuclei involved, their often insufficient selectivity in bonding the metal ion, their stability, their selectivity for the organ under' examination, or their biological tole ⁇ rability.
- Gd-DTPA/N-Methyl-D-glucamine is too quickly removed from the blood stream and from the lesions of the tissues under examination. This reduces the time available for obtaining images significant from diagnostic point of view. Moreover the diffusion of the contrast agent between the, healthy part and the diseased one is often so fast that the contrast between the two regions can be too weak. To overcome these difficulties, the problem has been ap ⁇ proached in many ways among which the most interesting are: a) Other chelating agents have been studied, in particular macrocyclic ones, of which the most effective proved to be 1,4,7,10-tetraazacyclododecane-N,N' ,N",N" '-tetra- acetic acid (DOTA).
- DOTA 1,4,7,10-tetraazacyclododecane-N,N' ,N",N" '-tetra- acetic acid
- Gadolinium and its chelating agents have been che ⁇ mically-conjugated to macromolecules such as, for in ⁇ stance, proteins (albumin, etc.), immunoglobulins, or to cellulose or other polymeric matrices.
- macromolecules such as, for in ⁇ stance, proteins (albumin, etc.), immunoglobulins, or to cellulose or other polymeric matrices.
- this generally improved the relaxivity of Gd, but on the other hand it was necessarily accompanied by a sub-optimal dosage, because of limitations in solubili ⁇ ty, toxicity and the substitution density of the macro ⁇ molecules.
- the chelating agents of formula I have shown an excellent scavenging capacity for metal ions even in very diluted solutions. A significant example of said property is the
- soluble and the poorly soluble compounds are suitable for oral or enteral administration, and therefore of particular usefulness for visualization of the gastrointestinal tract.
- parenteral administration they are preferably formulated as a sterile aqueous suspension or solution, whose pH can range for instance from 6.0 to 8.5. Said sterile aqueous suspensions or solutions can be administered in concentrations varying from 0.002 to 1.0 molar.
- Said formulations can also be lyophilized and supplied as such, to be reconstituted at the moment of their use.
- said agents can be formulated as a suspension or a solution containing additives suitable for instance to increase viscosity.
- chela ⁇ ted metal ions For oral administration they can be formulated according to preparation methods commonly used in pharmaceutical technology, optionally also as a coated formulation so as to have additional protection against the acid pH of the stomach, preventing in that way the release of the chela ⁇ ted metal ions which takes place in particular at the pH values typical of gastric juices.
- Other excipients such as sweetening or flavouring agents, can be added according to known pharmaceutical formulation techniques.
- Suspensions or solutions of complex salts can also be formulated as aerosols to be used in aerosol-bronchogra- phy.
- Some of the complex compounds of the invention have a surprising organ specificity, in that they particularly concentrate in the liver, in the spleen or, after intra- lymphatic, intraparenchymal, intramuscular or subcutaneous application, in the lymphatic vases and in the lymph no- des.
- the resulting contrast between the organ under examination and adjacent tissues permits improved imaging of said organ by N.M.R.
- metal complexes of the chelating agents object of the present invention can also be used as contrast agents in nuclear medicine and for electron spin resonance or echographic analyses.
- the metal central ions in the chelated complexes are, respectively, a radioisotope for
- A is preferably a ⁇ -hydroxy- ⁇ X-propionic, ⁇ -methoxy-Wrpropionic or ⁇ -benzylo- xy-O-propionic group, optionally esterified or preferably substituted by an amide residue which can be free, mono- or bi-substituted by alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl groups.
- R can preferably be H or a straight or branched alkyl group, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or a benzyl or a substituted benzyl group as. defined in formula I.
- R can also be an acyl or hydroxyacyl group.
- R can also be a polyoxaethylene group of formula H(OHCH_CH.)_ -, Me(OCH_CH.)_ -, o Et(OCH.CH.)_ -. 2 2 2-4 2 2 2-4 2 2 2-4 2 2-4
- X can be a hydroxy group or also a-O-R group, wherein R is as defined in formula I.
- R are the following: methyl, ethyl, isopropyl, 2-hydroxyethyl, 2-hydroxypropyl, 1,3-di- hydroxyisopropyl, polyoxaalkyl groups.
- X can preferably be also an hydroxyalkylamino group of formula -NR R , in which R and R are as defined in formula I.
- R and R are as defined in formula I.
- Non-limiting examples of said groups are the following ones: amino-, 2-hydroxyethylamino-, 2-hydroxypropylamino-,
- ⁇ ir preferably are an acetic or an ( -propionic group, eventually esterified or substituted by an amido residue which can be in the free form or mono- or bi-substituted by alkyl, hydroxyalkyl, alkoxyalkyl or alkoxyhydroxyalkyl groups.
- R can preferably be hydrogen or straight or branched lower alkyl, preferably methyl.
- R are the following: hydrogen, methyl, straight or branched propyl, butyl and pentyl groups, as defined in formula I.
- Y can preferably be a hydroxy group or a -O-R group, in which R has the above defined meanings of formula I.
- R_ are the following: methyl,
- Y can preferably be also a hydroxyalkylamino group of formula -NR R in which R and R have the above mentioned meanings of formula I.
- Non-limiting examples of said groups are the following ones: amino, 2-hydroxyethylamino-, 2-hydroxypropylamino-, 2,3- dihydroxypropylamino- 1,3-dihydroxyisopropylamino-, 1,3- dihydroxy-2-methyl-isopropylamino-, 2, 3,4-trihydroxy-l-bu- tyla ino-, 1,3,4-trihydroxy-2-butylamino-, 1,3-dihydro- xy-2-hydroxymethyl-isopropylamino-, N-methyl-N-2-hydroxy- ethylamino-, N-methyl-N-2,3-dihydroxypropylamino-, N-me- thyl-N-1,3-dihydroxyisopropylamino-, N-methyl-N-2,3,4,5,6- -pentahydroxyhexylamino-, N-2-hydroxyethyl-N-2,3-dihydro ⁇ xypropylamino-,
- Metal ions suited to form complex salts with the chelating agents of general formula I are mainly the di- or triva— lent ions of the elements having atomic numbers ranging from 20 to 31, 39, 42, 43, 44, 49, or from 57 to 83 and particularly preferred are Fe , Fe , Cu , Cr , perhaps,(3+) _ (3+) n (3+) M (2+) Gd , Eu , Dy or Mn
- metal radioisotopes particularly preferred are
- Preferred inorganic acid anions comprise ions such as chlorides, bromides, iodides or other ions such as sulfate.
- Preferred organic acid anions comprise ions of acids which are generally pharmaceutically used to salify basic substances, such as acetate, succinate, citrate, fumarate, maleate.
- Preferred inorganic base cations comprise alkali metal ions, such as lithium, potassium and sodium, the latter being particularly preferred.
- Preferred organic base cations comprise primary, secondary and tertiary amines, such as ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine and N-methyl- glucamine, the latter being preferred.
- Preferred amino acid cations comprise, for example, those of lysine, arginine and ornithine.
- Non-limiting examples of the macromolecules suited for conjugation with the chelate complexes of the invention are the following: biomolecules, such as hormones (insu ⁇ lin), prostaglandins, steroidal hormones, amino sugars, peptides, proteins (albumin, human serum albumin), lipids, antibodies such as monoclonal antibodies, polysaccharide chains.
- biomolecules such as hormones (insu ⁇ lin), prostaglandins, steroidal hormones, amino sugars, peptides, proteins (albumin, human serum albumin), lipids, antibodies such as monoclonal antibodies, polysaccharide chains.
- the chelated complexes of the invention can also be incorporated into liposomes, used "in form of mono- or multi-lamellar vescicles.
- the chelating agents of general * formula I and the complex salts thereof are preferably prepared by reacting 1, ,7,10-tetraazacyclododecane (II), prepared according to the method of Atkins et al. (JACS 96, 2268 (1974)),
- Compound IV can also be obtained, for example, by protect ⁇ ing diethylenetriamine V with a suitable protecting group P, wherein P can be, for example, a phthaloyl group or another appropriate protective group known in the literature (T.W. Greene: "Protective groups in organic synthesis”- 1980),
- Compound IV or the polysubstituted analogues thereof can in turn be subjected to condensation with the appropriate 0(-halo-acetic derivative VIII, or with a suitable precursor thereof (such as an ester or a nitrile).
- chelation of the desired metal ion is obtained preferably by reacting the appropriate derivative of for- mula I with the stoichiometric amount of metal, in form of a salt or an oxide, possibly in the presence of the base or acid amounts necessary for neutralization.
- Condensation of II with III is carried out preferably in water or in a dipolar aprotic organic solvent, such as dimethylformamide (DMF) or dimethylace amide (DMAC) or in a mixture thereof, at a temperature from 30 to 150°C, preferably from 40 to 100°C.
- a dipolar aprotic organic solvent such as dimethylformamide (DMF) or dimethylace amide (DMAC) or in a mixture thereof, at a temperature from 30 to 150°C, preferably from 40 to 100°C.
- Subsequent condensation of IV with VIII can be effected in an aqueous medium or in an organic solvent, in the presence of an appropriate inorganic or organic base, such as sodium hydroxide, potassium hydroxide, potassium carbo ⁇ nate or tetrabutylammonium hydroxide (TBAOH), at a pH ranging from 8 to 12, preferably from 9 to 11.
- an appropriate inorganic or organic base such as sodium hydroxide, potassium hydroxide, potassium carbo ⁇ nate or tetrabutylammonium hydroxide (TBAOH)
- TSAOH tetrabutylammonium hydroxide
- the temperature can range from 40 to 100°C , preferably from 50 to 70°C.
- a suspension of 17.2 g of 1,4,7,10-tetraazacyclodode ⁇ cane (0.1 mol) and of 71 g of sodium 2-chloro-3-ben- zyloxypropionate (0.3 mol) in 70 ml of water was heated to 50°C for 24 h.
- the resulting solution was diluted to 400 ml with water, dropped into 200 ml of 2N HCl, extracted several times with ethylene chloride and then was evaporated to dryness under vacuum.
- the crude residue was taken up into 400 ml of water and adsorbed on amberlite IR 120, from which it was eluted by means of 5N sodium hydroxide.
- EXAMPLE 2 2-/1, 4,7, 10-tetraaza-7-(l-carboxy-2-benzyloxy-ethyl)-cy- clododecane-l-yl7 ⁇ 3-benzyloxypropionic acid.
- the organic phase was evaporated to dryness and the resi ⁇ due was dissolved in 200 ml of 0.01N HCl and washed with ethyl ether..
- the pH was adjusted to 6 with 10% sodium hydroxide and the aqueous solution was evaporated to dryness.
- the crude residue was taken up into 30 ml of water and adsorbed on amberlite IR 120, from which it was eluted with 5N ammonium hydroxide. By concentration of the basic eluate, a residue of 7 g was obtained, which was crystallized from water.
- the mixture was heated to 50°O for 17 h and .the pH was kept at 10 by further additions of 6N sodium hydroxide.
- the solution was cooled and applied to amberlite IR 120, from which the product was eluted with 5N ammonium hydroxide.
- the basic eluate was evaporated to dryness, the resulting crude compound was dissolved in water and the solution was acidified to pH 3 with 5N HCl.
- the precipitate was filtered and crystallized from water to give the desired compound.
- D(-)-N-methylglucamine salt of the Gd /2-/I,4, 7,10-te- traaza-4, 7,10-tri(carboxymethyl)-cyclododecane-l-yl7-3-ben- zyloxypr ⁇ pionic acid complex To a suspension of 100 g of 2- ⁇ ,4,7,10-tetraaza-4,7,10- tri(carboxymethyl)-cyclododecane-l- l7 ⁇ 3-benzyloxypropionic acid (0.19 mol), obtained according to the process de ⁇ scribed in example 3, in 150 ml of water 36.6 g of D(-)-N-methylglucamine (0.187 mol) were added.
- the catalyst was removed by filtration and the aqueous solution was evaporated under vacuum at 50°C. Upon drying the residue to constant weight, the desired debenzylated compound was obtained.
- A Gd /2-/1,4, 7,10-tetraaza-4,7,10-tri(carboxyme ⁇ thyl)-cyclododecane-l-yl7-3-benzyloxypropionic acid, 15 neutralized with N-methylglucamine.
- An anhydrous lipidic mixture was prepared, having the following composition: egg phosphatidylcholine 75 mol % and cholesterol 25 mol % using the REV method (F. Szoka et al., (1978), Proc Natl. Acad. Sci. U.S.A. 75,4194).
- A Gd + /2-/1,4,7,10-tetraaza-4,7,10-tri(carboxy e- thyl)-cyclododecane-l-yl7 ⁇ 3-benzyloxypropionic acid, neu ⁇ tralized with N-methylglucamine.
- EXAMPLE 14 Preparation of a solution of D(-)-N-methylglucamine salt of Gd / 2-/1,4,7,10-tetraaza-4,7,10-tri(carboxymethyl)- -cyclododecane-l-yl7 ⁇ 3-benzyloxypropionic acid complex. 436.8 g (0.500 mol) of the compound obtained according to the procedure described in example 5 were dissolved in 300 ml of pro iniectione (p.i.) water. The solution volume was taken to 500 ml by addition of water p.i., then the solu ⁇ tion was filtered, put in vials and sterilized.
- pro iniectione p.i.
- EXAMPLE 15 Preparation of a solution of D(-)-N-methylglucamine salt of Gd / 2-/1,4,7,l ' O-tetraaza-4,7,10-tri(carboxymethyl)- -cyclododecane-l-yl7 ⁇ 3-hydroxypropionic acid complex. 398.8 g (0.500 mol) of the compound obtained according to the procedure described in example 6, were dissolved in 300 ml of water p.i.. The solution volume was taken to 500 ml by addition of water p.i., then the solution was filtered, put in vials -and sterilized.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT23217/87A IT1224416B (it) | 1987-12-24 | 1987-12-24 | Chelanti macrociclici e loro chelati |
IT2321787 | 1987-12-24 |
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Publication Number | Publication Date |
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EP0440606A1 true EP0440606A1 (en) | 1991-08-14 |
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EP89900817A Pending EP0440606A1 (en) | 1987-12-24 | 1988-12-16 | Macrocyclic chelating agents and chelates thereof |
EP88121087A Expired - Lifetime EP0325762B1 (en) | 1987-12-24 | 1988-12-16 | Macrocyclic chelating agents and chelates thereof |
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EP88121087A Expired - Lifetime EP0325762B1 (en) | 1987-12-24 | 1988-12-16 | Macrocyclic chelating agents and chelates thereof |
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EP (2) | EP0440606A1 (es) |
JP (1) | JP2744920B2 (es) |
KR (1) | KR900700467A (es) |
AT (1) | ATE120191T1 (es) |
DE (1) | DE3853415T2 (es) |
ES (1) | ES2070845T3 (es) |
IE (1) | IE67551B1 (es) |
IL (1) | IL88762A (es) |
IT (1) | IT1224416B (es) |
MX (1) | MX9203262A (es) |
NZ (1) | NZ227421A (es) |
PH (1) | PH26255A (es) |
WO (1) | WO1989005802A1 (es) |
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Families Citing this family (24)
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EP0466200B1 (en) * | 1987-07-16 | 1996-04-24 | Nycomed Imaging As | Aminocarboxylic acids and derivatives thereof |
DE4001655A1 (de) | 1990-01-18 | 1991-07-25 | Schering Ag | 6-ring enthaltende makrocyclische tetraaza-verbindungen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
US6039931A (en) * | 1989-06-30 | 2000-03-21 | Schering Aktiengesellschaft | Derivatized DTPA complexes, pharmaceutical agents containing these compounds, their use, and processes for their production |
US5695739A (en) * | 1989-06-30 | 1997-12-09 | Schering Aktiengesellschaft | Derivatized DTPA complexes, pharmaceutical agents containing these compounds, their use, and processes for their production |
DE4009119A1 (de) * | 1990-03-19 | 1991-09-26 | Schering Ag | 1,4,7,10-tetraazacyclododecan-butyltriole, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
US5162109A (en) * | 1990-09-13 | 1992-11-10 | Mallinckrodt Medical, Inc. | Magnetic resonance imaging agents |
DE4035760A1 (de) * | 1990-11-08 | 1992-05-14 | Schering Ag | Mono-n-substituierte 1,4,7,10-tetraazacyclododecan-derivate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
US6875864B2 (en) | 1991-08-01 | 2005-04-05 | Bracco International B.V. | Aminocarboxylate ligands having substituted aromatic amide moieties |
EP0565930A1 (en) * | 1992-03-27 | 1993-10-20 | Nihon Medi-Physics Co., Ltd. | Tetraazacyclododecane tetraacetic acid derivatives and the use thereof as diagnostic agents |
US5310535A (en) * | 1992-04-24 | 1994-05-10 | The Dow Chemical Company | Carboxamide modified polyamine chelators and radioactive complexes thereof for conjugation to antibodies |
EP0588229A3 (en) * | 1992-09-12 | 1994-06-15 | Hoechst Ag | Macrocyclic chelating agents for the preparation of technetium or rhenium complexes |
WO1995001346A1 (en) * | 1993-06-30 | 1995-01-12 | Akzo Nobel N.V. | Chelating compounds |
EP0702677A1 (en) * | 1994-04-08 | 1996-03-27 | BRACCO International B.V. | Aromatic amide compounds and metal chelates thereof |
US6693190B1 (en) | 1994-05-11 | 2004-02-17 | Bracco International B.V. | Enhanced relaxivity monomeric and multimeric compounds |
IT1274038B (it) * | 1994-07-29 | 1997-07-14 | Bracco Spa | Chelanti macrociclici loro chelati e relativi usi in campo diagnostico |
US5672335A (en) * | 1994-11-30 | 1997-09-30 | Schering Aktiengesellschaft | Use of metal complexes as liver and gallbladder X-ray diagnostic agents |
DE19507820A1 (de) * | 1995-02-21 | 1996-08-22 | Schering Ag | Neuartig substituierte DTPA-Derivate, deren Metallkomplexe, diese Komplexe enthaltende pharmazeutische Mittel, deren Verwendung in der Diagnostik, sowie Verfahren zur Herstellung der Komplexe und Mittel |
IT1291624B1 (it) * | 1997-04-18 | 1999-01-11 | Bracco Spa | Chelati complessi di metalli paramagnetici a bassa tossicita' |
IT1293777B1 (it) * | 1997-07-25 | 1999-03-10 | Bracco Spa | Processo per la preparazione di tetraazamacrocicli |
IT1293778B1 (it) * | 1997-07-25 | 1999-03-10 | Bracco Spa | 1,4,7,10-tetraazabiciclo(8.2.2.)tetradecan-2 one, sua preparazione e suo uso per la preparazione di tetraazamacrocicli |
DE19744004C1 (de) * | 1997-09-26 | 1999-07-22 | Schering Ag | Lipophile Metall-Komplexe für Nekrose und Infarkt-Imaging |
US6495118B1 (en) | 1997-09-26 | 2002-12-17 | Schering Aktiengesellschaft | Lipophilic metal complexes for necrosis and infarction imaging |
IT1297034B1 (it) | 1997-12-30 | 1999-08-03 | Bracco Spa | Acido 1,4,7,10-tetraazaciclododecan-1,4-diacetico |
IT1297035B1 (it) | 1997-12-30 | 1999-08-03 | Bracco Spa | Derivati dell'acido 1,4,7,10-tetraazaciclododecan-1,4-diacetico |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0281474A2 (en) * | 1987-02-28 | 1988-09-07 | Sumitomo Electric Industries Limited | Process for manufacturing a compound oxide-type superconducting wire |
EP0282286A2 (en) * | 1987-03-13 | 1988-09-14 | Kabushiki Kaisha Toshiba | Superconducting wire and method of manufacturing the same |
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NL194579C (nl) * | 1983-01-21 | 2002-08-05 | Schering Ag | Diagnostisch middel. |
DE3316703A1 (de) * | 1983-05-04 | 1984-11-08 | Schering AG, 1000 Berlin und 4709 Bergkamen | Orales kontrastmittel fuer die kernspintomographie und dessen herstellung |
US4639365A (en) * | 1984-10-18 | 1987-01-27 | The Board Of Regents, The University Of Texas System | Gadolinium chelates as NMR contrast agents |
DE3772785D1 (de) * | 1986-01-23 | 1991-10-17 | Squibb & Sons Inc | 1-substituiertes-4,7,10-triscarboxymethyl-1,4,7,10-tetraazacyclododecan und analoga. |
FR2596992B1 (fr) * | 1986-04-11 | 1988-12-16 | Guerbet Sa | Sel de lysine du complexe gadolinium-dota et ses applications au diagnostic |
DE3625417C2 (de) * | 1986-07-28 | 1998-10-08 | Schering Ag | Tetraazacyclododecan-Derivate |
-
1987
- 1987-12-24 IT IT23217/87A patent/IT1224416B/it active
-
1988
- 1988-12-16 ES ES88121087T patent/ES2070845T3/es not_active Expired - Lifetime
- 1988-12-16 EP EP89900817A patent/EP0440606A1/en active Pending
- 1988-12-16 AT AT88121087T patent/ATE120191T1/de not_active IP Right Cessation
- 1988-12-16 EP EP88121087A patent/EP0325762B1/en not_active Expired - Lifetime
- 1988-12-16 DE DE3853415T patent/DE3853415T2/de not_active Expired - Lifetime
- 1988-12-16 WO PCT/EP1988/001166 patent/WO1989005802A1/en not_active Application Discontinuation
- 1988-12-16 JP JP1500736A patent/JP2744920B2/ja not_active Expired - Lifetime
- 1988-12-20 NZ NZ227421A patent/NZ227421A/xx unknown
- 1988-12-22 IL IL8876288A patent/IL88762A/en not_active IP Right Cessation
- 1988-12-22 PH PH37968A patent/PH26255A/en unknown
- 1988-12-22 IE IE384488A patent/IE67551B1/en not_active IP Right Cessation
- 1988-12-22 ZA ZA889597A patent/ZA889597B/xx unknown
-
1989
- 1989-08-25 KR KR1019890701612A patent/KR900700467A/ko not_active Application Discontinuation
-
1992
- 1992-06-24 MX MX9203262A patent/MX9203262A/es unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0281474A2 (en) * | 1987-02-28 | 1988-09-07 | Sumitomo Electric Industries Limited | Process for manufacturing a compound oxide-type superconducting wire |
EP0282286A2 (en) * | 1987-03-13 | 1988-09-14 | Kabushiki Kaisha Toshiba | Superconducting wire and method of manufacturing the same |
Non-Patent Citations (1)
Title |
---|
JAPANESE JOURNAL OF APPLIED PHYSICS, vol. 26, no. 10, October 1987, pages 1653-1656, Tokyo, JP; O. KOHNO et al.: "Critical current density of Y-Ba-Cu oxide wires" * |
Also Published As
Publication number | Publication date |
---|---|
KR900700467A (ko) | 1990-08-13 |
ES2070845T3 (es) | 1995-06-16 |
DE3853415D1 (de) | 1995-04-27 |
IT8723217A0 (it) | 1987-12-24 |
EP0325762B1 (en) | 1995-03-22 |
IL88762A (en) | 1995-07-31 |
JPH03501848A (ja) | 1991-04-25 |
MX9203262A (es) | 1992-07-01 |
ZA889597B (en) | 1989-09-27 |
IT1224416B (it) | 1990-10-04 |
ATE120191T1 (de) | 1995-04-15 |
IE883844L (en) | 1989-06-24 |
WO1989005802A1 (en) | 1989-06-29 |
PH26255A (en) | 1992-04-01 |
IL88762A0 (en) | 1989-07-31 |
NZ227421A (en) | 1990-10-26 |
DE3853415T2 (de) | 1995-08-31 |
JP2744920B2 (ja) | 1998-04-28 |
IE67551B1 (en) | 1996-04-17 |
EP0325762A1 (en) | 1989-08-02 |
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