Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/04—X-ray contrast preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
  • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
  • A61K49/10—Organic compounds
  • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
  • A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T436/00—Chemistry: analytical and immunological testing
  • Y10T436/24—Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Definitions

• Novel substituted DTPA derivatives their metal complexes, pharmaceuticals containing these complexes
• the invention relates to novel substituted DTPA derivatives and their metal complexes, pharmaceutical compositions containing these complexes and their use in diagnostics and therapy.
• Contrast agents are indispensable aids in modern diagnostics; many diseases would not be diagnosed without the use of contrast agents. Contrast agents can be found in all areas of diagnostics such as X-ray, radio or ultrasound diagnostics or magnetic resonance imaging.
• the choice of the preferred method depends in part on according to the diagnostic question, but is also determined by the available device options for the doctor. Magnetic resonance imaging in particular, due to the considerable technical and associated high cost, does not yet have the widespread use of other methods, e.g. X-ray diagnostic methods found.
• the choice of a suitable contrast medium also varies depending on the particular question.
• the suitability of the contrast medium for a specific task is determined not least by its accumulation and distribution behavior in the organism. Although great progress has been made both in terms of equipment technology and on the contrast agent side, satisfactory solutions are not yet available for all questions.
• Contrast agents based on triiodobenzene have been able to establish themselves in X-ray diagnostics, since these compounds have a high X-ray density, low general and local toxicity and are very readily water-soluble.
• the shadowing effect of an X-ray contrast medium essentially depends on the size of the mass attenuation coefficient of the elements contained in the compound in the diagnostic radiation range.
• X-ray contrast agent Besides j odiern compounds and complexes of metals of higher atomic number are suitable as X-ray contrast agent.
• Physiologically compatible complex compounds of these metals are already widely used in the field of NMR diagnostics. These are generally metal complexes, as are described, for example, in EP 0071 564.
• WO 93/16375 describes metal complexes which are linked to iodine-substituted aromatics via amide bonds. These compounds should allow both NMR and X-ray examinations to be carried out with only one application of the contrast medium. A combination of the two imaging methods is advantageous in many cases for a differentiated representation and a reliable determination of certain diseases. These compounds are said to be particularly suitable for angiography. The compounds show how the reworking of the preparation examples showed however, insufficient accumulation in the area of the liver for X-ray examinations.
• Radiodiagnostics or radiotherapy - especially for X-ray diagnostics of the liver - are suitable.
• R 1 represents a radical of the formula la
• R 2 is independently a hydrogen atom or a branched or unbranched, saturated or unsaturated
• R 3 represents a hydrogen atom or a branched or unbranched, saturated or unsaturated C 1 -C 6 radical or a carboxyl group
• L 1 represents a direct bond or a C 1 -C 4 alkylene chain
• L 2 , L 3 each independently from each other for a direct bond
• Oxygen atom a sulfur atom or a C 1 -C 10 alkylene chain which is optionally interrupted by one to three oxygen and / or one to three sulfur atoms,
• R 4 , R 5 independently of one another represent a hydrogen atom or a group R 1 or
• R 4 and R 5 together, including the common amide nitrogen atom, form a four- to eight-membered ring which can contain two further oxygen atoms and / or two carbonyl groups,
• X 2 independently of one another represents a hydrogen atom or a metal ion equivalent of an element of atomic numbers 20-32, 39-51 or 57-83,
• contrast media for the X-ray diagnostics in particular for X-ray diagnostics of the liver, bile ducts and bile, are suitable.
• the invention therefore relates to the compounds of the general formula I.
• the central ion must be derived from an element with a higher atomic number in order to achieve sufficient absorption of the X-rays. It has been found that elements of atomic numbers 57-83 are particularly suitable for this purpose. Complexes of the elements lanthanum, gadolinium, terbium, dysprosium, holmium, erbium, ytterbium, lutetium, bismuth, lead and hafnium are very particularly suitable.
• the central ion must be paramagnetic. It was found that, for this purpose, in particular the chromium (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III) -, Samarium (lll) - and the ytterbium (lll) ion are suitable. Complexes of the ions gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II) are particularly preferred.
• the central ion must be radioactive.
• the radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, strontium, technetium, indium, ytterbium, gadolinium, samarium, silver, gold, rhenium, bismuth and iridium are suitable.
• the metals gallium, indium and technetium are particularly preferred.
• the radicals R 4 and R 5 can independently of one another be hydrogen atoms or radicals of the formula R 1 .
• Suitable compounds are, for example, compounds in which one or two of the carboxylic acid groups present in the molecule are present as alkylamides (for example methyl, ethyl, propyl or butylamides).
• benzylamides or derivatives thereof for example methoxybenzylamide, ethoxybenzylamide, propoxybenzylamide, butoxybenzylamide, benzyloxybenzylamide, methylbenzylamide, ethylbenzylamide, propylbenzylamide, butylbenzylamide or benzylamide.
• the radicals R 4 and R 5 can also, together with the amide nitrogen atom, the substituents of which they are, form a four- to eight-membered ring which can contain zero to two further oxygen atoms and / or zero to two further carbonyl or sulfonyl groups. If R 4 and R 5 together represent a ring system, the morpholine ring or the S, S-dioxothiomorpholine ring is preferred.
• amide functions are not negatively charged.
• the charge of the complex changes when a carboxyl function is converted to an amide function.
• carboxyl functions are converted into amide functions that an electrically neutral complex is formed.
• Lipophilic radicals which are described by the formula Ia are used as radicals R 1 of the general formula I.
• Favorable properties are in particular those radicals which contain aromatic groups or are interrupted by aromatic groups.
• the radicals R 1 can also contain the heteroatoms oxygen and / or sulfur, it never being possible for two heteroatoms to be bonded to one another.
• substituted benzyl radicals can be used as radicals R 1 , such as, for example, methoxybenzyl, ethoxybenzyl, propoxybenzyl, butoxybenzyl, pentoxybenzyl, benzyloxybenzyl, methylbenzyl, ethylbenzyl, propylbenzyl, butylbenzyl, pentylbenzyl and benzyl groups.
• R 1 such as, for example, methoxybenzyl, ethoxybenzyl, propoxybenzyl, butoxybenzyl, pentoxybenzyl, benzyloxybenzyl, methylbenzyl, ethylbenzyl, propylbenzyl, butylbenzyl, pentylbenzyl and benzyl groups.
• the butylbenzyl radical is particularly suitable.
• the R 1 radicals can also contain several heteroatoms, such as, for example, (ethoxy) ethoxybenzyl, 2- (2-ethoxyethoxy) ethoxybenzyl, 2- (methoxy) ethoxybenzyl and ((ethoxy) ethoxy) methoxybenzyl radicals, preferably is the ethoxybenzyl radical.
• the benzyl radicals can be substituted in the 2-, 3-, or 4-position, that is to say ortho, meta or para. Ortho and para-substituents are preferred, para-radicals are very particularly preferred.
• the complexing agent has more acid functions than the complexed metal carries positive elementary charges.
• the 3,6,9-triaza-3,6,9-tris (carboxymethyl) -2- (4-ethoxybenzyl) -undecanedioic acid described in Example 1 carries five acid groups, while the dysprosium in the dysprosium oxide (Dy 2 0 3 ) is in the oxidation state + III.
• Dy 2 0 3 the dysprosium in the dysprosium oxide
• a complex is thus formed which also contains two dissociable protons, an acid complex. Two protons and one dianion - formed from the metal and the complexing agent - are thus present in aqueous solution.
• physiologically compatible cations are sodium * , calcium 2 * , magnesium 2 * and zinc 2 * and organic cations of the bases meglumine, glucosamine, arginine, omithin, lysine and ethanolamine.
• the complexes according to the invention are prepared in the manner as has been disclosed in the patents EP 71564, EP 130934 and DE-OS 3401052 by using the metal oxide or a metal salt (for example a chloride, nitrate, acetate, carbonate or sulfate) Elements of the ordinal numbers 20-32, 39-51 or 57-83 in water and / or another polar solvent (such as methanol, ethanol, isopropanol or N, N-dimethylformamide) dissolves or suspends and with the solution or suspension the equivalent amount of the complexing agent of the general formula II
• a metal salt for example a chloride, nitrate, acetate, carbonate or sulfate
• Elements of the ordinal numbers 20-32, 39-51 or 57-83 in water and / or another polar solvent such as methanol, ethanol, isopropanol or N, N-dimethylformamide
• R 1 has the meanings given above, X 1b independently of one another for a HO or group
• N (R 4 ) R 5 with R 4 , R 5 have the meaning given above, are reacted and then, if desired, acidic hydrogen atoms present from acid groups are substituted by cations of inorganic and / or organic bases or amino acids.
• the neutralization takes place with the help of inorganic bases (e.g.
• Hydroxides, carbonates, or bicarbonates) of, for example, sodium, calcium or lithium and / or organic bases such as, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, glucamine, N-methyl- and N, N-dimethylglucamine, and also basic Amino acids such as lysine, arginine and ornithine.
• bases such as, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, glucamine, N-methyl- and N, N-dimethylglucamine, and also basic Amino acids such as lysine, arginine and ornithine.
• neutral complex salts for example, the acidic complex salts in aqueous solution or suspension can be added with enough of the desired bases that the neutral point is reached. The solution obtained can then be evaporated to dryness in vacuo.
• acidic complexes contain several free acidic groups, it is often expedient to prepare neutral mixed salts which contain both inorganic and organic cations as counterions.
• the order of base addition can also be reversed.
• Another way to get neutral complex compounds is to remove the remaining acid groups, e.g. described in EP 0450742 to convert all or part of it into amides.
• the complexes can be prepared from the complexing agents by the methods described in "Radiotracers for Medical Applications", Vol. I, CRC Press, Boca Raton, Florida. Preparation of the complexing agents according to the invention
• R 1 has the meanings given above,
• the invention further relates to agents which contain at least one of the compounds according to the invention and a process for the preparation of these agents, which is characterized in that the complex salt dissolved in water with the additives and stabilizers customary in galenics in a for the enteral or parenteral application is brought into a suitable form so that the complex salt is present in a concentration of 1 to 1500 mmol / l, preferably in a concentration of 10 to 1000 mmol / l. It is often advantageous if the pharmaceutical composition contains a small excess (0.1 to 10 mol% based on the diagnostically active metal complex) of complexing agents.
• the pharmaceutical agent contains small additions (0.1 to 10 mol% based on the diagnostically active metal complex) of metal complexes of weakly bound metals.
• metal complexes of weakly bound metals In particular sodium, calcium, magnesium and zinc complexes are suitable as additives in this sense. They can be used in the form of complexes with the complexing agents according to the invention, but also in the form of metal complexes with other complexing agents, such as DTPA, EDTA, TTHA and derivatives thereof.
• the resulting agents are then sterilized if desired. Depending on the diagnostic question, they are usually applied in a dose of 1 to 300 ml.
• Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), small additions of complexing agents (such as diethylenetriaminepentaacetic acid) or, if necessary, electrolytes such as. B. sodium chloride or, if necessary, antioxidants such as. B. ascorbic acid.
• physiologically acceptable buffers such as tromethamine
• complexing agents such as diethylenetriaminepentaacetic acid
• electrolytes such as. B. sodium chloride or, if necessary, antioxidants such as. B. ascorbic acid.
• suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral administration or other purposes, they are mixed with one or more adjuvants common in galenics (e.g. methyl cellulose, lactose, mannitol) and / or surfactants (for example, lecithins, Tweens ® , Myrj ® and / or flavoring agents for flavor correction (eg essential oils) mixed.
• adjuvants common in galenics
• surfactants for example, lecithins, Tweens ® , Myrj ® and / or flavoring agents for flavor correction (eg essential oils) mixed.
• the invention therefore also relates to processes for the preparation of the complex compounds and their salts.
• the final security is cleaning the isolated complex salt.
• the substances according to the invention fulfill the diverse requirements that are to be placed on contrast agents in modern diagnostics.
• the compounds and means made from them are characterized by:
• 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 the ions which are not covalently bound in the complexes - in themselves toxic - within the time in which the new contrast medium are completely excreted, did not occur.
• the complex compounds according to the invention have a positive effect in X-ray diagnostics in that they surprisingly permit examinations with short-wave X-rays than is possible with conventional contrast agents, which means that the radiation exposure of the Patients are significantly reduced, as is known, soft radiation from the tissue is absorbed much more strongly than hard (R. Felix, Das Röntgensent; Thieme Stuttgart 1980).
• the complexes of the following metals according to the invention are particularly suitable for use in X-ray diagnostics: gadolinium, terbium,
• the agents are also particularly suitable for digital subtraction techniques (which work with higher tube voltages).
• the compounds according to the invention are distinguished by improved cardiovascular compatibility in comparison with other complex compounds.
• the agents according to the invention which contain a paramagnetic metal ion in the complex, can be used not only in X-ray diagnostics but also in NMR diagnostics. This dual character opens up further areas of application. Thus, these agents according to the invention are always to be used with advantage when a combination of X-ray and NMR diagnostics is required for the differentiated presentation and reliable determination of certain diseases. This applies, for example, in the case of suspected recurrence after tumor surgery or radiation therapy. In these cases, the patient is treated by using a contrast agent that works for both Techniques are equally suitable, an additional burden of double application saves.
• the complexing agents according to the invention and their complexes with weakly bound metals are also suitable for removing heavy metals (such as cadmium, mercury, thallium, lead) from the body remove, for example after heavy metal poisoning.
• weakly bound metals such as Na * , Ca 2 * , Mg 2 * , Zn 2 *
• heavy metals such as cadmium, mercury, thallium, lead
• the mixture is taken up in toluene and shaken out several times against aqueous sodium hydrogen carbonate solution.
• the organic phase is separated off, dried over magnesium sulfate, filtered and evaporated.
• the oily residue is chromatographed for purification on silica gel with hexane / diethyl ether triethylamine.
• the product fractions are evaporated in a vacuum and dried. Yield: 12.7 g (90.3% of theory) of colorless oil.
• Example f 7.59 g (20 mmol) of the compound prepared according to Example d) and 11.2 g (22 mmol) of 3, 6-D iaza-3- (tert-butoxycarbony imethy I) -6- (2-bromethy I) octane iso di-tert-butyl ester (Example f) are placed in 45 ml of acetonitrile and mixed with 25 ml of 2N phosphate buffer solution (pH 8.0). The mixture is stirred vigorously at room temperature for 22 hours, the aqueous phosphate buffer phase being replaced with fresh buffer solution after 2 and 7 hours.
• 2N phosphate buffer solution pH 8.0
• the aqueous solution is mixed with 3.79 g (9.61 mmol) of ytterbium oxide and stirred at 95 ° C.
• the mixture is filtered, adjusted to pH 7.2, stirred with 0.2 g of activated carbon at 90 ° C. for ten minutes, filtered again and the filtrate is lyophilized. Yield: 12.8 g (93.8% of theory) of colorless lyophilisate.

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