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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention relates to the articles characterized in the claims, namely perfluoroalkyl-containing metal complexes with nitrogen-containing radicals of the general formula I, processes for their preparation and their use in NMR and X-ray diagnostics, radiodiagnostics and radiotherapy, as well as in MRI lymphography and blood pool imaging ,
• the perfluoroalkyl-containing metal complexes are used in nuclear magnetic resonance imaging (MRI) for the representation of various physiological and pathophysiological structures and thus for improving the diagnostic information, namely the localization and the degree of the disease, selection and success monitoring of a targeted therapy and for prophylaxis.
• MRI nuclear magnetic resonance imaging
• the compounds according to the invention are particularly suitable for lymphography, for tumor diagnosis and for infarct and necrosis imaging.
• fluorine-containing compounds which can be used for imaging are described in US 5,362,478 (VIVORX), US Patent 4,586,511, DE 4008179 (Schering), WO 94/05335 and WO 94/22368 (both Molecular Biosystems), EP 292 306 (TERUMO Kabushiki Kaisha) EP 628 316 (TERUMO Kabushiki Kaisha) and DE 4317566 (Schering).
• Magnetic resonance imaging Magnetic resonance imaging (Magnevist®, Prohance®, Omniscan®, Dotarem®).
• lymph node metastases are found in about 50-69% of all patients with malignant tumors (Elke, Lymphographie, in: Frommhold, Stender, Thurn (eds.), Radiological diagnostics in clinic and practice, Volume IV, Thieme Verlag Stuttgart, 7th ed., 434-496, 1984).
• CT computed tomography
• US and MRI magnetic resonance imaging methods
• lymph nodes with metastatic involvement and hyperplastic lymph nodes could be distinguished.
• fluorescence-labeled dextrans are also used in animal experiments in order to observe the lymphatic drainage after their interstitial application. All common markers for the presentation of lymphatic and lymph nodes after interstitial / intracutaneous administration is therefore common that they are substances with a particulate character ("particulates”, eg emulsions and nanocrystal suspensions) or large polymers (see also WO 90/14846). , however, because of their lack of local and systemic tolerability as well as their low lymphatic activity, which results in insufficient diagnostic efficiency, the preparations described so far have not proven to be optimally suitable for indirect lymphography.
• the lymphatic system according to the present invention includes both the lymph nodes and the lymphatic vessels.
• the substances of the present invention are therefore suitable for the diagnosis of changes in the lymphatic system, preferably for the diagnosis of changes in the lymph nodes and / or lymphatic vessels, in particular diagnosis of metastases in the lymph nodes.
• lymph-specific contrast agents which make it possible to display both the primary tumor and a possible lymph node metastasis in a diagnostic session.
• myocardial infarction is not a stationary process, but a dynamic process that extends over a longer period (weeks to months).
• the disease occurs in approximately three phases, which are not sharply separated, but overlapping.
• the first phase the development of myocardial infarction, involves the 24 hours after the infarction, in which the destruction progresses from the subendocardium to the myocardium like a shockwave (wave front phenomenon).
• the second phase the existing infarct, involves the stabilization of the area where fiber formation (fibrosis) occurs as a healing process.
• the third phase, the healed infarct begins after all destroyed tissue has been replaced by fibrous scar tissue.
• Infarcts occur not only in the myocardium, but also in other tissues, especially in the brain.
• necrosis While the infarct can be cured to some extent, necrosis, the localized tissue death, can only prevent or at least alleviate the harmful effects on the residual organism. Necrosis can occur in many ways: through injury, chemicals, oxygen deficiency or radiation. As with the infarction, the knowledge of the extent and type of necrosis is important for the further medical procedure. Early on, therefore, attempts were made to improve the localization of infarcts and necroses by using contrast agents in non-invasive procedures such as scintigraphy or magnetic resonance imaging. In the literature, the attempts to use porphyrins for to insert the necrosis imaging, a large space. The results obtained, however, give a contradictory picture. In addition, porphyrins tend to deposit in the skin, resulting in photosensitization.
• Non-porphyrin scaffold-derived contrast agents for necrosis and infarct imaging are described in DE 19744003 (Schering AG), DE 19744004 (Schering AG) and WO 99/17809 (EPIX). So far, however, there are still no compounds that can be used satisfactorily as a contrast agent in infarction and necrosis imaging and are also characterized by excellent tolerability.
• the object of the invention was therefore to provide contrast media which on the one hand have outstanding imaging properties as MRI contrast agents, and in particular for tumor and necrosis imaging and / or lymphography and / or blood pool imaging and / or for the presentation of thrombi or atherosclerotic plaques, while being excellent in compatibility.
• the object of the invention is achieved by the perfluoroalkyl-containing complexes with nitrogen-containing linker structure of the general formula I.
• R represents either a mono- or oligosaccharide radical linked via the 1-OH, in which case Q has the meaning of a group selected from: ⁇ -CO- (CH 2 ) n - ⁇ ⁇ -NH- (CH 2) n.- ⁇ ⁇ - (CH 2) m - ⁇ wherein n "is an integer of 1 and 5 and m is an integer of 1 and 6, and
• ⁇ indicates the binding site to the linker L and ⁇ the binding site to the radical R;
• R has one of the following meanings, then Q has the meaning of a direct
• R is a polar radical selected from
• R 7 is H or C 1 -C 4 -alkyl
• R f is a perfluorinated, straight-chain or branched carbon chain of the formula -C n F 2n E, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n represents the numbers 4-30,
• R 1 is a hydrogen atom or a metal ion equivalent of the atomic numbers
• R 2 and R 3 are independently hydrogen, C 1 -C 7 -AlkVl, benzyl, phenyl, -CH 2 OH or -CH 2 OCH 3 represent and
• U is -C 6 H 4 -O-CH 2 -CO-, - (CH 2) -Q L5, a phenylene group, -CH 2 -NHCO-CH 2 -
• R 4 is hydrogen or a metal ion equivalent mentioned under R 1 and U 1 -C 6 H 4 -O-CH 2 -O- or a group - (CH 2 ) P -, where ⁇ the binding site to -CO- and p 'is an integer between 1 and 4.
• R 1 and R 2 have the abovementioned meaning
• R 1 has the abovementioned meaning
• U 2 is an optionally imino, phenylene, phenyleneoxy, phenyleneimino, amide, hydrazide, carbonyl, ester groups, oxygen, sulfur and / or Nitrogen atom (s) - containing, optionally substituted by hydroxy, mercapto, oxo, thioxo, carboxy, carboxyalkyl, ester, and / or amino group (s) substituted straight-chain or branched, saturated or unsaturated C 1 -C Represents 2 O alkylene group,
• optionally present free acid groups may optionally be present as salts of organic and / or inorganic bases or amino acids or amino acid amides,
• L represents a radical selected from the following radicals IXa) to IXc):
• n 'and m' independently represent an integer between 0 and 4, and m '+ n'> 1;
• m '+ n' is 1, 2, or 3;
• R 8 and R 8 are independently either -H or -OH, where m '+ n'> 1, any group - (CR 8 R 8 ) - may be different, and W is either a direct bond, -O- or a Phenylene group which may optionally be substituted by 1 to 4 hydroxy groups,
• ⁇ is the binding site of L to the complex K
• ⁇ is the binding site of L to the radical Q
• ⁇ represents the binding site of L to the radical X
• Y is a direct bond, a group -CO- or a group NR 6 , wherein R 6 is -H or a linear or branched, saturated or unsaturated C 1 -C 15 carbon chain which is of 1-4 O atoms, 1-3 -NHCO groups, 1-3 -CONH groups, 1-2 -SO 2 groups, 1-2 sulfur atoms, 1-3 -NH groups or 1-2 phenylene groups optionally with 1-2 OH groups, 1-2 NH 2 groups, 1-2 -COOH groups, or 1 -2 -SO 3 H groups may be substituted, may be interrupted,
• G is either -O- or -SO 2 -
• s and s' independently of one another are either 1 or 2
• t is either 0 or 1 and
• p represents the binding site of X to L and ⁇ represents the binding site of X to R f ,
• R 6 is H or a C 1 -C 6 alkyl group which may be interrupted by 1-3 O atoms and which may be substituted by 1-4 -OH groups.
• R 6 is a C 1 -C 4 alkyl group.
• G is the group -O-.
• t 0.
• W is a direct bond
• the radical R bound to the linker L via a -CO-, -NR 7 - or a direct bond is a carbon chain having 1-30 C atoms which is interrupted by 1 to 10 oxygen atoms and / or substituted with 1-10 OH groups.
• R is a -CO-, -NR 7 - bonded or direct bond to L C1 - C12 carbon chain that is interrupted 1-6 oxygen atoms and / or substituted with 1-6 -OH groups. If the compound according to the invention is intended for use in NMR diagnosis, then the metal ion of the signaling group must be paramagnetic. These are in particular the divalent and trivalent ions of the elements of atomic numbers 21-29, 42, 44 and 58-70.
• Suitable ions are the chromium (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III ) and ytterbium (III) ion. Because of their strong magnetic moment, particularly preferred are gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III), and manganese (II) ions ,
• the metal ion must be radioactive.
• radioisotopes of the elements of atomic numbers 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 and 77 are suitable.
• Preferred are technetium, gallium, indium, rhenium and yttrium.
• the metal ion is preferably derived from an element of a higher atomic number in order to achieve sufficient absorption of the X-rays. It has been found that for this purpose diagnostic agents containing a physiologically compatible complex salt with metal ions of elements of atomic numbers 25, 26 and 39 and 57-83 are suitable.
• Any azide hydrogen atoms present in R 1 may optionally be replaced in whole or in part by cations of inorganic and / or organic bases or amino acids or amino acid amides.
• Suitable inorganic cations are, for example, the lithium ion, the potassium ion, the calcium ion and in particular the sodium ion.
• Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as Ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and especially N-methylglucamine.
• Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine and the amides of otherwise acidic or neutral amino acids.
• Particularly preferred compounds of general formula I are those having macrocycle K of general formula II.
• the radical U in the metal complex K is preferably -CH 2 - or C 6 H 4 -O-CH 2 - (O, where ⁇ represents the point of attachment to -CO-.
• U 2 is a C 1 -C 6 alkylene chain which is optionally interrupted by 1 to 2 -NHCO groups and / or 1 to 2 O atoms, and which may be substituted by 1 to 3 -OH groups.
• the radical U 2 in the metal complex K is particularly preferably a linear alkylene group having 1 to 6 C atoms, in particular 2, 3 or 4 C atoms, or a linear alkylene group having 1 to 6 C atoms, in particular 2, 3 or 4 C - atoms which is interrupted by 1 O atom, or a linear alkylene group having 1 to 6 C atoms, in particular 2, 3 or 4 C atoms, which contains an -NHCO group.
• U 2 is an ethylene group.
• alkyl groups R 2 and R 3 in the macrocycle of the general formula II may be straight-chain or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1, 2
• R 2 and R 3 are independently
• R 2 is methyl and R 3 is
• R is a monosaccharide radical having 5 or 6 C atoms, preferably glucose, mannose, galactose, ribose, arabinose or xylose or their deoxysugars such as 6-deoxygalactose (fucose) or 6-deoxymannose (rhamnose) or their peralkylated derivatives.
• Particularly preferred are glucose, mannose and galactose, in particular mannose.
• R is selected from one of the following radicals:
• R ' is either H or CH 3 and R "is either H or a C 1 to C 4 alkyl radical
• p is 1, 2, 3, or 4.
• the polar residues listed here are purchased goods or are presented according to methods described in the literature.
• R is a radical attached via -CO- to L of the formula: -C (O) CH 2 O [(CH 2 ) 2 O] p R '
• R' is the group CH 3 .
• Q has the meaning of a group selected from: ⁇ -CO- (CH 2 ) n - ⁇ where n "is an integer of 1 and 5, and and L at the same time has the meaning of a group of the formula IXa or IXb.
• Q has the meaning of a group selected from: ⁇ -NH- (CH 2 ) n. - ⁇ where n "is an integer of 1 and 5, and and L also has the meaning of a group IXc.
• R f -C n F 2n + 1 means; ie E in the formula -C n F 2n E denotes a fluorine atom, n preferably represents the numbers 4-15.
• Very particularly preferred are the radicals -C 4 F 9 , -C 6 F 13 , -C 8 F 17 , -C 12 F 25 and -C 14 F 29 and the radicals of the compounds mentioned in the examples.
• the nitrogen-containing radical L in the general formula I which represents the "skeleton" means in a preferred embodiment of the invention the amino acid residue (Vc).
• the nitrogen-containing radical L in the general formula I represents a diamine radical of the formula (IXb) or (IXa).
• R 5 is a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl protecting group, and R 2 , R 3 and U have the meaning given
• R 5 and R 2 have the meaning mentioned or a carboxylic acid of the general formula Va or Vb
• R 5 has the meaning given
• R 5 has the meaning mentioned or a carboxylic acid of the general formula VIIa
• the mixture of metal complex carboxylic acid MIb used in the coupling reaction, optionally containing carboxy and / or hydroxy groups in protected form, and at least one solubilizing agent in an amount of up to 5, preferably 0.5-2 molar equivalents based on the metal complex carboxylic acid can be used both in an upstream reaction stage prepared and isolated (for example by evaporation, freeze-drying or spray-drying of an aqueous or water-miscible solution of the ingredients or by precipitation with an organic solvent from such a solution) and then reacted in DMSO with dehydrating reagent and optionally a coupling excipient may also be formed in situ, if appropriate, by addition of solubilizing substance (s) to the DMSO suspension of metal complex carboxylic acid, dehydrating reagent and optionally a coupling excipient.
• solubilizing substance (s) to the DMSO suspension of metal complex carboxylic acid, dehydrating reagent and optionally a coupling excipient.
• the reaction solution prepared by one of these methods is for pretreatment (acid activation) 1 to 24, preferably maintained for 3 to 12 hours at temperatures of 0 to 50 ° C, preferably at room temperature.
• radicals L, R, R f , Q, and X have the meanings given above, without solvent or dissolved, for example in dimethyl sulfoxide, alcohols such as methanol, ethanol, isopropanol or mixtures thereof, formamide, dimethylformamide, water or mixtures of listed solvents, preferably in dimethyl sulfoxide, in water or in solvents mixed with water.
• the reaction solution thus obtained is maintained at temperatures of 0 to 70 ° C, preferably 30 to 60 ° C, 1 to 48, preferably 8 to 24 hours.
• a base such as e.g. Triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, tripropylamine, tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate.
• the protective groups which may still be present are subsequently split off.
• the isolation of the reaction product is carried out by the methods known in the art, preferably by precipitation with organic solvents, preferably acetone, 2-butanone, diethyl ether, ethyl acetate, methyl t-butyl ether, isopropanol or mixtures thereof. Further purification can be carried out, for example, by chromatography, crystallization or ultrafiltration.
• organic solvents preferably acetone, 2-butanone, diethyl ether, ethyl acetate, methyl t-butyl ether, isopropanol or mixtures thereof.
• Suitable solubilizing substances are alkali metal, alkaline earth metal, trialkylammonium, tetraalkylammonium salts, ureas, N-hydroxyimides, hydroxyaryltriazoles, substituted phenols and salts of heterocyclic amines.
• dehydrating reagents are all known in the art means.
• Examples include carbodiimides and onium reagents such.
• DCCI Dicyclohexylcarbodiimide
• EDC 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide-hydroxychloride
• BOP benzotriazole-i-yloxytris
• BOP benzotriazole-i-yloxytri
• Suitable coupling auxiliaries to be used are all those which are known to the person skilled in the art (Houben-Weyl, Methods of Organic Chemistry, Vol. XV / 2, Georg Thieme-Verlag, Stuttgart, 1974). Examples which may be mentioned are 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, 3,5-dinitrophenol and pentafluorophenol. Preference is given to 4-nitrophenol and N-hydroxysuccinimide, the first-mentioned reagent being particularly preferred.
• the cleavage of the protective groups is carried out by the methods known to those skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous-alcoholic solution at temperatures from 0 ° to 50 ° C, acid hydrolysis with mineral acids or in the case of e.g. Tert-butyl esters with the aid of trifluoroacetic acid.
• hydrolysis hydrogenolysis
• acid hydrolysis with mineral acids or in the case of e.g. Tert-butyl esters with the aid of trifluoroacetic acid.
• Tert-butyl esters with the aid of trifluoroacetic acid.
• the carboxylic acids of the general formulas IIa to VIIa used are either known compounds or are prepared by the processes described in the examples, see DE 10040381 and DE 10040858. Thus, the preparation of the carboxylic acids of general formula IIa from DE 196 52 386 is known.
• the carboxylic acids of the general formula Villa used are prepared as described in WO 95/17451.
• the perbenzylated sugar acids used as starting materials when R is a monosaccharide or oligosaccharide can be prepared analogously to Lockhoff, Angew. Chem. 1998, 110 No. 24, p. 3634ff. Getting produced.
• R is a monosaccharide or oligosaccharide
• 1-O-acetic acid of perbenzyl glucose over 2 stages, via trichloroacetimidate and reaction with hydroxyacetic acid ethyl ester, BF 3 catalysis in THF and subsequent saponification with NaOH in MeOH / THF.
• the perbenzylated sugar acids used as starting materials can also be prepared by dissolving the perbenzylated 1-OH sugars in a water-immiscible organic solvent and with an alkylating reagent of general formula XI
• a nucleofuge in the alkylating reagent of general formula XVIII for example, the radicals -Cl, -Br, -J, -OTs, -OMs, -OSO 2 CF 3 , -OSO 2 C 4 F 9 or -OSO 2 C 8 F 17 may be included ,
• the protecting group is a common acid protecting group. These protecting groups are well known to those skilled in the art (Protective Groups in Organic Syntheses, Second Edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc., New York 1991).
• the inventive reaction can be done 0 C to room temperature at temperatures ranging from 0-50 c C, preferably from O.
• the reaction times are from 10 minutes to 24 hours, preferably from 20 minutes to 12 hours.
• the base is added either in solid form, preferably finely powdered, or as a 10-70%, preferably 30-50%, aqueous solution.
• Preferred bases are NaOH and KOH.
• Suitable organic, water-immiscible solvents in the alkylation process according to the invention include toluene, benzene, CF 3 -benzene, hexane, cyclohexane, diethyl ether, tetrahydrofuran, dichloromethane, MTB or mixtures thereof.
• phase transfer catalysts used in the process according to the invention known for this purpose quaternary ammonium or phosphonium salts or crown ethers such. [15] Crown-5 or [18] Crown-6.
• Quaternary ammonium salts having four identical or different hydrocarbon groups on the cation selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl, are preferably suitable.
• the hydrocarbon groups on the cation must be large enough to ensure good solubility of the alkylating reagent in the organic solvent. Particular preference is given according to the invention to N (butyl) 4 + -Cl " , N (butyl) 4 + -HSO 4 ' , but also N (methyl) 4 + -CI ' .
• the cleavage of the protective groups is carried out by the methods known to those skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous-alcoholic solution at temperatures from 0 ° to 50 ° C, acid hydrolysis with mineral acids or in the case of e.g. Tert-butyl esters with the aid of trifluoroacetic acid.
• hydrolysis hydrogenolysis
• acid hydrolysis with mineral acids or in the case of e.g. Tert-butyl esters with the aid of trifluoroacetic acid.
• Tert-butyl esters with the aid of trifluoroacetic acid.
• XVIII for example, the radicals -Cl, -Br, -J, -OTs, -OMs, -OSO 2 CF 3 , -OSO 2 C 4 F 9 or
• the cleavage of the protective groups is carried out by the methods known to those skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous-alcoholic solution at temperatures from 0 ° to 50 ° C, acid hydrolysis with mineral acids or in the case of e.g. Tert-butyl esters with the aid of trifluoroacetic acid.
• hydrolysis hydrogenolysis
• acid hydrolysis with mineral acids or in the case of e.g. Tert-butyl esters with the aid of trifluoroacetic acid.
• Tert-butyl esters with the aid of trifluoroacetic acid.
• the cleavage of the protective groups is carried out by the methods known to those skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous-alcoholic solution at temperatures from 0 ° to 50 ° C, acid hydrolysis with mineral acids or in the case of e.g. Tert-butyl esters with the aid of trifluoroacetic acid.
• hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous-alcoholic solution at temperatures from 0 ° to 50 ° C acid hydrolysis with mineral acids or in the case of e.g. Tert-butyl esters with the aid of trifluoroacetic acid.
• Such double-protected amino acids of the general formula (XVII) are purchased goods (Bachern).
• the compounds according to the invention are particularly suitable for use in NMR and X-ray diagnostics, radiodiagnostics and radiotherapy, as well as in MRI lymphography and for blood pool imaging.
• the perfluoroalkyl-containing metal complexes are Particularly suitable for use in nuclear magnetic resonance imaging (MRI) for the representation of various physiological and pathophysiological structures and thus for improving the diagnostic information, such as the location and degree of the disease, for the selection and success of a targeted therapy and for the prophylaxis of diseases and disorders.
• MRI nuclear magnetic resonance imaging
• the substances according to the invention are used for MRI lymphography.
• the substances according to the invention are used for blood pool imaging.
• Suitable diseases and disorders include tumor diseases, in particular detection and characterization of primary tumors, femoral metastases, necroses, cardiovascular diseases, in particular changes in vessel diameter such as stenoses and aneurysms, atherosclerosis by detection of atherosclerotic plaques, thromboembolic diseases, infarcts, necrosis, inflammation , in particular arthritis, osteomyelitis, ulcerative colitis, as well as nerve damage.
• the substances according to the invention are used for necrosis or tumor imaging.
• the invention also relates to pharmaceutical compositions containing at least one physiologically acceptable compound of the invention, optionally with the additives customary in galenicals.
• the compounds of the present invention are characterized by excellent compatibility and at the same time excellent imaging properties. They are therefore particularly well suited for systemic use in MRI, in particular in MRI lymphography and in tumor imaging.
• the preparation of the pharmaceutical compositions according to the invention is carried out in a manner known per se by reacting the complex compounds according to the invention, if appropriate with the addition of the additives customary in galenicals - suspended or dissolved in an aqueous medium and, if appropriate, the suspension or solution is sterilized.
• suitable additives are for example physiologically acceptable buffers (such as tromethamine), additions of complexing agents or weak complexes (such as diethylenetriaminepentaacetic acid or the corresponding to the metal complexes of the invention Ca complexes) or - if necessary - electrolytes such as sodium chloride or - if necessary - Antioxidants such as ascorbic acid.
• suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral or parenteral administration or other purposes, they are mixed with one or more excipients customary in galenics [for example methyl cellulose, lactose, mannitol] and / or surfactant (s) [for example, lecithins, Tween ®, Myrj ®] and / or flavoring substance (s) [for example, ethereal oils] for taste correction mixed.
• galenics for example methyl cellulose, lactose, mannitol
• surfactant for example, lecithins, Tween ®, Myrj ®
• flavoring substance for example, ethereal oils
• the invention therefore also relates to processes for the preparation of the complex compounds and their salts. As last certainty remains a cleaning of the isolated complex.
• agents according to the invention may be administered together with a suitable carrier such as, for example, serum or saline and together with another protein such as, for example, human serum albumin (HSA).
• a suitable carrier such as, for example, serum or saline
• another protein such as, for example, human serum albumin (HSA).
• the agents according to the invention are usually administered parenterally, preferably IV. They may also be administered intravascularly or interstitially / intracutaneously, depending on whether body vessels or tissues are to be examined.
• the pharmaceutical compositions according to the invention preferably contain 0.1 ⁇ mol - 2 mol / l of the complex and are usually dosed in amounts of 0.0001 - 5 mmol / kg.
• compositions of the invention meet the diverse requirements for suitability as a contrast agent for magnetic resonance imaging. Thus, they are ideally suited to improve after oral or parenteral administration by increasing the signal intensity of the image obtained using the magnetic resonance imaging in its validity. They also demonstrate the high potency needed to stress the body with the least amount of foreign matter and the excellent tolerability necessary to maintain the non-invasive nature of the studies.
• the good solubility in water and low osmolality of the compositions according to the invention makes it possible to produce highly concentrated solutions in order to keep the volume load of the circulation within acceptable limits and to compensate for the dilution by the body fluid.
• the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of bound in the complexes - in itself toxic - ions within the time in which the new contrast agents completely excreted again, only very slowly.
• the agents according to the invention are dosed for use as NMR diagnostic agents in amounts of 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg.
• the complex compounds according to the invention can be used advantageously as susceptibility reagents and as shift reagents for in vivo NMR spectroscopy.
• the agents according to the invention are also suitable as radiodiagnostics. Details of such application and dosage will e.g. in "Radiotracers for Medical Applications", CRC Press, Boca Raton, Florida.
• the compounds and agents according to the invention can also be used in positron emission tomography, the positron-emitting isotopes such as 43sc, 44sc, 52pe, 55 Co, 68 Ga and 86 Y are used (Heiss, WD, Phelps, ME, Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).
• the contrast agents according to the invention can therefore also be used to display abnormal
• the compounds of the invention are characterized in particular by the fact that they are completely eliminated from the body and thus are extremely well tolerated. Thus, the excellent imaging properties can be utilized and the non-invasive nature of the diagnosis maintained.
• the substances according to the invention can also support the radiation therapy of malignant tumors. This differs from the corresponding diagnosis only by the amount and type of isotope used.
• the goal is the destruction of tumor cells by high-energy short-wave radiation with the shortest possible range.
• interactions of the metals contained in the complexes such as iron or gadolinium
• ionizing radiation eg X-rays
• neutron beams are exploited. This effect significantly increases the local radiation dose at the site where the metal complex is located (eg in tumors).
• the metal complex conjugates according to the invention are therefore also suitable as a radiosensitizing substance in the radiotherapy of malignant tumors (eg exploitation of Mössbauer effects or in neutron capture therapy).
• Suitable ⁇ -emitting ions are for example 46 Sc, 47 Sc 1 48 Sc, 72 Ga, 73 Ga and 90 Y.
• Suitable low-half-life ⁇ -emitting ions are for example 21 1 Bi, 212 Bi, 213 Bi and 214 Bi, wherein 212 Bi is preferred.
• a suitable photon and electron emitting ion is 1 58 Gd, which can be obtained from 157 Gd by neutron capture.
• the agent according to the invention is for use in the method described by RL Mills et al. (Nature Vol. 336, (1988), p. 787], the central ion must be derived from a Mössbauer isotope, such as, for example, 57p e oc j er 151
• u .
• agents according to the invention may be administered together with a suitable carrier such as, for example, serum or saline and together with another protein such as, for example, human serum albumin.
• a suitable carrier such as, for example, serum or saline and together with another protein such as, for example, human serum albumin.
• the dosage depends on the type of cellular disorder, the metal ion used and the type of imaging method.
• agents according to the invention are usually administered parenterally, preferably i.v. They may also be administered intravascularly or interstitially / intracutaneously, as previously discussed, depending on whether body vessels or tissues are to be examined.
• compositions according to the invention are outstandingly suitable as X-ray contrast agents, it being particularly noteworthy that they do not show any signs of the anaphylactic reactions known from the iodine-containing contrast agents in biochemical-pharmacological investigations. They are particularly valuable because of the favorable absorption properties in higher-voltage regions for digital subtraction techniques.
• the agents according to the invention are dosed for use as X-ray contrast agents in analogy to, for example, meglumine diatrizoate in amounts of 0.1-5 mmol / kg, preferably 0.25-1 mmol / kg.
• metal ion equivalent as used in the application is a common and well-known term in the field of complex chemistry.
• a metal ion equivalent is one equivalent of metal ions which can bind to, for example, a carboxylate group instead of hydrogen, for example, one Gd 3+ may be attached to 3 carboxylate groups ie 1/3 Gd 3+ corresponds to the metal ion equivalent R 1 in formula (II), (III), (IV) or (V) when the metal is gadolinium. Examples
• Ethanol is added 2.29 g (23.75 mmol) of methanesulfonic acid and 4.0 g of palladium
• Tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1, 4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775 , Schering AG, (Example 1)) are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 0 C is added 5.86 g
• reaction solution is mixed with 500 ml of ethyl acetate and 300 ml of water.
• organic phase is separated and washed twice with 300 ml of water washed, then dried over magnesium sulfate and evaporated to dryness in vacuo.
• the residue is dissolved in a mixture consisting of 400 ml of methanol and
• reaction mixture is worked up by treatment with Amberlite IR 120 (H + -).
• Dicyclohexylcarbodiimid stirred for 3 h at 0 0 C and then for 16 h at room temperature.
• Tris (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1, 4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775 , Schering AG, (Example 1)) are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 0 C is 4.92 g
• N-hydroxysuccinimide in 200 ml of dimethylformamide is added at 0 0 C 8:05 g (39.04 mmol)
• Dicyclohexylcarbodiimid stirred for 3 h at 0 0 C and then for 16 h at room temperature.
• Tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1, 4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775 , Schering AG, (Example 1)) are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 0 C is added 5.81 g
• Ethanol is added 2.0 g (20.72 mmol) of methanesulfonic acid and 3.0 g of palladium catalyst
• Reaction solution is mixed with 400 ml of 1 N hydrochloric acid, and stirred well for 15 min.
• the organic phase is separated off, dried over magnesium sulfate and added in vacuo to
• Dicyclohexylcarbodiimid stirred for 3 h at 0 0 C and then for 16 h at room temperature.
• Ethanol is added 2.0 g of palladium catalyst (10% Pd / C) and hydrogenated for 24 h
• Tris (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1, 4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775 , Schering AG 1 (Example 1)) are dissolved with gentle heating in 100 ml of dimethyl sulfoxide. At 10 0 C is added 2.76 g
• Tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1, 4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775 , Schering AG, (Example 1)) are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 1O 0 C., 4.87 g
• Reaction solution is mixed with 400 ml of 1 N hydrochloric acid, and stirred well for 15 min.
• the organic phase is separated off, dried over magnesium sulfate and added in vacuo to
• Tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1, 4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775 , Schering AG, (Example 1)) are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 1O 0 C., 4.78 g
• Ethanol is added 2.28 g (23.63 mmol) of methanesulfonic acid and 4.0 g of palladium
• Tris (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1, 4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775 , Schering AG, (Example 1)) are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 0 C is added 5.13 g
• Dicyclohexylcarbodiimid stirred for 3 h at 0 0 C and then for 16 h at room temperature.
• Ethanol is added 2.23 g (23.16 mmol) of methanesulfonic acid and 4.0 g of palladium
• Tris (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1, 4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775 , Schering AG, (Example 1)) are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 0 C are added 4.46 g
• Ethanol is added 2.40 g (24.86 mmol) of methanesulfonic acid and 4.0 g of palladium
• Dicyclohexylcarbodiimid stirred for 3 h at 0 0 C and then for 16 h at room temperature.
• Tris (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1, 4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775 , Schering AG, (Example 1)) are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 1O 0 C., 04.14 g
• Ethanol is added 2.25 g (23.29 mmol) of methanesulfonic acid and 4.0 g of palladium
• Dimethylformamide are added at 0 0 C 7.71 g (37.4 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 0 C and then for 16 h at room temperature. It is filtered from the precipitated
• Tris- (carboxylatomethyl) -10- [1-carboxy-3-aza-4-oxo-5-methylpentan-5-yl] -1, 4,7,10-tetraazacyclododecane, Gd complex (WO 98/24775 , Schering AG, (Example 1)) are dissolved in 200 ml of dimethyl sulfoxide with gentle heating. At 10 c C is 4.72 g
• Butyloxycarbonyl-3-oxa-pentylenediamine (Koenig et al., Eur. J. Org. Chem., 2002, 3004-
• Dichloromethane is added at 0 0 C 50 ml of trifluoroacetic acid and 3 h at room temperature.
• ACROS Aminoethyl 2,2-dimethyl- [1,3-dioxolan-4-yl] methylamine
• reaction solution is filtered off from insoluble constituents, evaporated to dryness in vacuo and the residue is chromatographed on silica gel (mobile phase:
• Dimethylformamide are added at 0 0 C 3.65 g (17.7 mmol) of dicyclohexylcarbodiimide, stirred for 3 h at 0 C C and then 16 h at room temperature. It is filtered from the precipitated
• Dichloromethane is added at 0 0 C 50 ml of trifluoroacetic acid and 3 h at room temperature.
• Example 30 Acute toxicity after single intravenous administration in mice (orienting)
• Example 32 Plasma kinetics after intravenous administration in rats
• Example 33 Presentation (MRI) of lymph node metastases and primary tumor after intravenous administration of the contrast agent in VX2 tumor-bearing rabbits
• FIGS. 1 and 2 show MR images of iliac lymph nodes pre-contrast and up to 24 h after intravenous administration of 50 .mu.mol Gd / kg body weight of Title substance from Example 1d) in rabbits with an implanted VX2 tumor.
• - Weighted turbo spin-echo images illustrate the strong signal increase in healthy lymph node tissue at early time points after contrast administration (15 to 60 min pi). Zones without signal increase within the lymph node were diagnosed as metastases and confirmed histologically (H / E staining of the lymph node sections) ( Figure 1).
• Example 34 MRI presentation of arteriosclerotic plaques after intravenous administration of the contrast agent in rats
• the images of Figure 3 show MR images of the aorta 6 and 24 h after intravenous administration of 50 .mu.mol Gd / kg body weight of the title substances from Example 1dj and Example 14c in Watanabe rabbit (WHHL rabbit, genetically induced arteriosclerosis) and in control animals without atherosclerosis (White New Zealanders).
• Example 35 MRI presentation of inflammatory lesions and necrotic areas after intravenous administration of the contrast agent in rats
• FIG. 4 show, by way of example, MR images of inflammatory muscle lesions and necrotic areas at different times after intravenous administration of 50 ⁇ mol Gd / kg body weight of the title substance from Example 14c in rats.
• the inflammation / necrosis was induced by intravenous administration of Rose Bengal (20 mg / kg, 24 h before contrast administration) and subsequent 20 min irradiation with a xenon lamp.
• -weighted turbo spin-echo images 1.5 T;
• Example 36 MRI presentation of lymph nodes after intravenous administration of the contrast agent in rats
• the figures show examples of MR images of popliteal lymph nodes at different times after intravenous administration of 50 .mu.mol Gd / kg body weight of the title substance from Example 5c) title substance from Example 14c) and title substance from Example 15c) in rats.
• -weighted turbo spin-echo images (1.5 T;
• T1-TSE illustrate the strong signal increase in the functional lymph node tissue at early times (up to 60 min p.i.).
• R1 (w) R1 -relaxivity in water
• R2 (w) R2 relaxivity in water

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