WO1991012822A1 - Zubereitungen für die mr-diagnostik - Google Patents
Zubereitungen für die mr-diagnostik Download PDFInfo
- Publication number
- WO1991012822A1 WO1991012822A1 PCT/EP1991/000382 EP9100382W WO9112822A1 WO 1991012822 A1 WO1991012822 A1 WO 1991012822A1 EP 9100382 W EP9100382 W EP 9100382W WO 9112822 A1 WO9112822 A1 WO 9112822A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salts
- iron
- preparations
- iii
- complexes
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000003745 diagnosis Methods 0.000 title claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 150000001768 cations Chemical class 0.000 claims abstract description 14
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002872 contrast media Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 5
- HNKGLEWRFGKTOY-UHFFFAOYSA-N (5-hydroxy-6-methyl-4-oxo-1h-pyridin-3-yl)methyl dihydrogen phosphate Chemical compound CC=1NC=C(COP(O)(O)=O)C(=O)C=1O HNKGLEWRFGKTOY-UHFFFAOYSA-N 0.000 claims description 5
- -1 2-methyl-3,4-dihydroxy-5-pyridyl ethylphosphoric acid Chemical compound 0.000 claims description 5
- 229940039231 contrast media Drugs 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- HEXISKMNITVSOI-UHFFFAOYSA-N (3-hydroxy-4-oxo-1h-pyridin-2-yl)methyl dihydrogen phosphate Chemical compound OC1=C(COP(O)(O)=O)NC=CC1=O HEXISKMNITVSOI-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 abstract description 3
- 229910006069 SO3H Inorganic materials 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- 230000005298 paramagnetic effect Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ACJKRVYMYKPSQR-UHFFFAOYSA-N 2-(chloromethyl)-3,4-bis(phenylmethoxy)pyridine Chemical compound C=1C=CC=CC=1COC=1C(CCl)=NC=CC=1OCC1=CC=CC=C1 ACJKRVYMYKPSQR-UHFFFAOYSA-N 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- JEJUWAJDWLOXCA-UHFFFAOYSA-N (3-hydroxy-4-oxo-1h-pyridin-2-yl)methylphosphonic acid Chemical class OC1=C(CP(O)(O)=O)NC=CC1=O JEJUWAJDWLOXCA-UHFFFAOYSA-N 0.000 description 1
- 0 *C(C1=O)=CNC(*)=C1O Chemical compound *C(C1=O)=CNC(*)=C1O 0.000 description 1
- UOTMYNBWXDUBNX-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinolin-2-ium;chloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 UOTMYNBWXDUBNX-UHFFFAOYSA-N 0.000 description 1
- IXAZNYYEGLSHOS-UHFFFAOYSA-N 2-aminoethanol;phosphoric acid Chemical compound NCCO.OP(O)(O)=O IXAZNYYEGLSHOS-UHFFFAOYSA-N 0.000 description 1
- ZCUUVWCJGRQCMZ-UHFFFAOYSA-N 3-hydroxypyridin-4(1H)-one Chemical class OC1=CC=NC=C1O ZCUUVWCJGRQCMZ-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- PLNKUDNDNPVDLK-UHFFFAOYSA-N CCC(CC)(C1=C(C(=O)C=CN1)O)P(=O)(O)O Chemical class CCC(CC)(C1=C(C(=O)C=CN1)O)P(=O)(O)O PLNKUDNDNPVDLK-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 125000005595 acetylacetonate group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229960000958 deferoxamine Drugs 0.000 description 1
- 229940099217 desferal Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000005291 magnetic effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 125000005499 phosphonyl group Chemical group 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- GGOZGYRTNQBSSA-UHFFFAOYSA-N pyridine-2,3-diol Chemical class OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- IWOLVLSIZCEOHM-UHFFFAOYSA-M silver;dibenzyl phosphate Chemical compound [Ag+].C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 IWOLVLSIZCEOHM-UHFFFAOYSA-M 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/02—Iron compounds
- C07F15/025—Iron compounds without a metal-carbon linkage
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Definitions
- the invention relates to new preparations for MR diagnostics.
- EP-A-0303555 discloses complexes of ethanolamine phosphoric acid with iron (III) and manganese (II) which are intended for prophylaxis and therapy.
- EP-A-0173163 proposes the use of metal complexes with phosphonyl organophosphinates for MR diagnosis.
- EP-A-0290047 describes measurement tall complexes of dipyridoxyl phosphoric acids as MR contrast agents.
- EP-A 0325559 discloses a process for the preparation of transition metal chelate complexes, in which a complex of the transition metal with a ⁇ -dicarbonyl compound, such as e.g. Acetylacetone, with which chelate is reacted to displace the ß-dicarbonyl compound.
- a complex of the transition metal with a ⁇ -dicarbonyl compound such as e.g. Acetylacetone
- the invention relates to preparations for MR diagnosis containing complexes of the compounds of the general formula I,
- R1 hydrogen and C1-C4-alkyl, R2 -P0 (0H) 2 , -0P0 (0H) 2 and -S0 3 H and
- X is a single bond and - (CH) -, where n is 1 and 2, with iron (III) and manganese (II) and / or their salts with cations of strong bases.
- R1 hydrogen and C1-C4-alkyl, R2 -P0 (0H) 2 , -0P0 (0H) z and -S0 3 H and
- X denotes a single bond and - (CH) -, where n stands for 1 and 2, with iron (III) and manganese (II) and / or their salts with cations of strong bases.
- Another preferred subject matter is preparations for MR diagnosis containing complexes of and 3,4-dihydroxy-2-pyridylmethylphosphoric acid with iron (III) and their salts with cations of strong bases.
- the salts of the complexes are preferably the sodium and N-methylglucamine salts.
- Another object of the invention is the use of the complexes of the compounds of general formula I and / or their salts with cations of strong bases for the production of contrast media for MR diagnostics.
- the preparations according to the invention result in a very good increase in contrast in MR diagnostics and are distinguished from the prior art by numerous advantages: they do not cause a reduction in blood pressure and heart rate in the dosages relevant for MR diagnostics. They are quickly excreted by the kidneys. They are not sensitive to hydrolysis. They are easier and less expensive to manufacture, and solutions with a phiological pH can be produced.
- Preparations according to the invention for MR diagnostics contain one or more of the complexes of the compounds of the general formula I and, if desired, customary additives.
- 3-hydroxy-4-pyridon-5-yl-methylphosphoric acids are known or can be prepared from available substances by processes known per se. It could be formulated in a tautomeric form as 3,4-dihydroxypyridines.
- 3,4-Dihydroxy-2-pyridylmethylphosphoric acid can also be used, for example, in addition to the method described in Drugs of the Future _14 [1989] 611 by condensing 3,4-bisbenzyloxy-2-chloromethylpyridine with silver dibenzylphosphate and hydrogenating it (4-fold debenzyl generation) with hydrogen on Pd / C in ethyl acetate.
- 3,4-dihydroxy-2-pyridylmethylphosphonic acids can be carried out using the method described in J. Med. Chem. 32 [1989] 1529 from 3,4-bisbenzyloxy-2-chloromethylpyridines by reaction with triethylphosphite, following the hydrogenation to the diethyl-3,4-bishydroxy-2-pyridylmethylphosphonates and cleavage with 6N hydrochloric acid to the free 3,4-dihydroxy-2-pyridylmethylphospho acids.
- the complexes are prepared in a manner known per se by adding iron (III) or manganese (II) salt in water and / or alcohol, such as methanol,
- Ethanol, etc. dissolves and stirred with the appropriate amount of pyridone or a pyroxide salt, optionally with heating to 50 ° C. to 120 ° C., until the reaction is complete. If the complex formed is insoluble in the solvent used, it crystallizes and can be filtered off. If the complex is soluble in the solvent used, it can be isolated by evaporating the solution to dryness or precipitated by adding another organic solvent. The complex compound obtained is then dissolved or suspended in water and mixed with the desired inorganic or organic base or acid until the neutral point is reached. After filtration of undissolved portions, the solution is evaporated and the desired complex salt is obtained as a residue. Alternatively, the complex salt can be precipitated by adding an organic solvent. The salts of the complexes are obtained, for example, by reaction with strong bases.
- the complexes can also be prepared in a manner known per se by adding an aqueous solution of the iron (III) or manganese (II) salt to a solution of the corresponding amount of pyridone plus the corresponding amount of base , e.g. Sodium hydroxide, added dropwise and the aqueous solution of the sodium salt of the complex sterile filtered. After stencil filtration, the complexes can be precipitated in the form of their salts by adding a non-polar water-miscible solvent (e.g. acetone or isopropanol). In this way, the desired complex salts are obtained in solid form free of inorganic salts.
- a non-polar water-miscible solvent e.g. acetone or isopropanol
- the complexes can also by the process specified in EP-A 0325559 by reacting appropriate ß-dicarbonyl complexes, e.g. the acetylacetonato complexes, with a pyridone or a pyridone salt.
- the complex can be precipitated by mineral acid (e.g. aqueous hydrochloric acid) at pH 2.5-3 and filtered. If desired, the complex can be added as a salt by adding a water-miscible organic solvent, e.g. Acetone or isopropanol.
- mineral acid e.g. aqueous hydrochloric acid
- the complex can be added as a salt by adding a water-miscible organic solvent, e.g. Acetone or isopropanol.
- the precipitated complex compound is dissolved in Suspended water and mixed with the appropriate amount of strong base (eg sodium hydroxide solution or N-methylglucamine).
- strong base eg sodium hydroxide solution or N-methylglucamine
- the new contrast agents which is a further subject of the invention, are produced in a manner known per se by dissolving the complexes and / or their salts in water or physiological saline solution and, if desired, additives customary in galenics, such as, for example, physiologically compatible buffer solutions (eg sodium dihydrogen phosphate solution), albumin or the like, is added and the solution is sterilized.
- physiologically compatible buffer solutions eg sodium dihydrogen phosphate solution
- albumin e.gly compatible buffer solutions
- the solutions can be filled into ampoules as they are or be frozen freeze-dried into a soluble powder.
- the aqueous solutions are adjusted to a pH with sufficient local tissue tolerance, for example to a pH of 7 to 9.
- the aqueous solutions are administered orally or parenterally, especially in vasal.
- aqueous solutions which contain the paramagnetic complex in a concentration of 30 to mmol / liter. About 1 to 300 ⁇ mol of the complex per kg body weight are administered per application. For an adult, IV use turns out to be a dose of 1 to 100 moles.
- Figure 1 shows the MR image of a rat with a CNS lesion injected with 0.3 mmol / Gd-DTPA.
- Fig. 2 shows the MR image of the same rat, which was about 15 minutes after the I Gd-DTPA 0.3 mmol / kg of an aqueous solution of the iron (III) complex of 2-methyl-3,4-dihydroxy-5-pyridylmethylphosphoric acid were injected.
- Gd-DTPA does not lead to a representation of the CNS lesion
- the preparation according to the invention allows a detailed representation of the lesion.
- the location of the lesion is indicated by an arrow in FIGS. 1 and 2.
- the UV maximum is 463 nm.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Radiology & Medical Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH656/90-3 | 1990-03-02 | ||
CH65690 | 1990-03-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1991012822A1 true WO1991012822A1 (de) | 1991-09-05 |
Family
ID=4192088
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1991/000382 WO1991012822A1 (de) | 1990-03-02 | 1991-03-01 | Zubereitungen für die mr-diagnostik |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0517765A1 (de) |
AU (1) | AU7346091A (de) |
WO (1) | WO1991012822A1 (de) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0494616A1 (de) * | 1991-01-07 | 1992-07-15 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Kontrastmittel für die MR-Diagnostik |
US5731299A (en) * | 1992-05-29 | 1998-03-24 | The Procter & Gamble Company | Phosphonosulfonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
US6932960B2 (en) | 2002-02-05 | 2005-08-23 | Bristol-Myers Squibb Pharma Company | N-substituted 3-hydroxy-4-pyridinones and pharmaceuticals containing thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2497731A (en) * | 1947-07-09 | 1950-02-14 | Merck & Co Inc | 2-methyl-3,4-dihydroxy-5-phosphonoxymethyl-pyridine and method for preparing same |
EP0159194A2 (de) * | 1984-04-19 | 1985-10-23 | National Research Development Corporation | Eisen-3-Hydroxypyron- oder 3-Hydroxypyridon-Komplexe und diese enthaltende pharmazeutische Zusammensetzungen |
EP0235361A2 (de) * | 1986-02-06 | 1987-09-09 | Salutar, Inc. | Ferrioxamine paramagnetische Kontrastagenzien für magnetische Resonanzbildformung |
EP0275215A1 (de) * | 1987-01-16 | 1988-07-20 | Guerbet S.A. | Kontrastmittel für den Gastrointestinaltrakt |
EP0290047A2 (de) * | 1987-05-08 | 1988-11-09 | Nycomed Salutar, Inc. | Dipyridoxyl-Phosphat als magnetisches Kernresonanz-Bildgebungsmittel |
EP0325559A2 (de) * | 1988-01-20 | 1989-07-26 | Ciba-Geigy Ag | Verfahren zur Herstellung von Komplexverbindungen |
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1991
- 1991-03-01 WO PCT/EP1991/000382 patent/WO1991012822A1/de active Search and Examination
- 1991-03-01 AU AU73460/91A patent/AU7346091A/en not_active Abandoned
- 1991-03-01 EP EP91905071A patent/EP0517765A1/de not_active Withdrawn
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2497731A (en) * | 1947-07-09 | 1950-02-14 | Merck & Co Inc | 2-methyl-3,4-dihydroxy-5-phosphonoxymethyl-pyridine and method for preparing same |
EP0159194A2 (de) * | 1984-04-19 | 1985-10-23 | National Research Development Corporation | Eisen-3-Hydroxypyron- oder 3-Hydroxypyridon-Komplexe und diese enthaltende pharmazeutische Zusammensetzungen |
EP0235361A2 (de) * | 1986-02-06 | 1987-09-09 | Salutar, Inc. | Ferrioxamine paramagnetische Kontrastagenzien für magnetische Resonanzbildformung |
EP0275215A1 (de) * | 1987-01-16 | 1988-07-20 | Guerbet S.A. | Kontrastmittel für den Gastrointestinaltrakt |
EP0290047A2 (de) * | 1987-05-08 | 1988-11-09 | Nycomed Salutar, Inc. | Dipyridoxyl-Phosphat als magnetisches Kernresonanz-Bildgebungsmittel |
EP0325559A2 (de) * | 1988-01-20 | 1989-07-26 | Ciba-Geigy Ag | Verfahren zur Herstellung von Komplexverbindungen |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0494616A1 (de) * | 1991-01-07 | 1992-07-15 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Kontrastmittel für die MR-Diagnostik |
WO1992011840A1 (de) * | 1991-01-07 | 1992-07-23 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Kontrastmittel für die mr-diagnostik |
US5731299A (en) * | 1992-05-29 | 1998-03-24 | The Procter & Gamble Company | Phosphonosulfonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
US6932960B2 (en) | 2002-02-05 | 2005-08-23 | Bristol-Myers Squibb Pharma Company | N-substituted 3-hydroxy-4-pyridinones and pharmaceuticals containing thereof |
Also Published As
Publication number | Publication date |
---|---|
EP0517765A1 (de) | 1992-12-16 |
AU7346091A (en) | 1991-09-18 |
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