DE3633243A1 - Phosphonate complexes - Google Patents

Abstract

Physiologically acceptable compounds of the general formula I <IMAGE> in which n represents the numbers 0, 1 or 2, m represents the numbers 0 or 1, R<1> and R<2> represent hydrogen atoms, lower alkyl groups, phenyl groups, benzyl groups, or, if n represents the number 0, together represent a trimethylene or a tetramethylene group, R<3> represents a hydrogen atom, a bromine atom, a fluorine atom, a hydroxyl, cyanide, phenyl or halophenyl group, R<4> represents a hydrogen atom or a PO3Z<1>Z<2> group, X represents a hydrogen atom and/or a metal ion equivalent, Z<1> and Z<2> independently of one another represent a C1-C6-alkyl radical and/or X, Y represents a COOX- or <IMAGE> group, A represents a straight-chain or branched, saturated or unsaturated C1-C10-alkylene group which is optionally interrupted by a cyclohexyl group and optionally substituted by a cyanide, hydroxyl, phenyl, halophenyl, benzyl, C1-C6-alkyl or C1-C6-O-alkyl group, and their salts with organic and/or inorganic bases are valuable complexing agents, complexes and complex salts.

Description

The invention relates to the subject matter characterized in the claims, d. H. new complexing agents, complexes and complex salts, these compounds containing agents, their use in diagnostics and methods for Manufacture of these compounds and agents.

Metal complexes were already used as a contrast medium for the early 1950s Radiology has been considered. The connections used at that time but were so toxic that use in humans was out of the question came. It was therefore very surprising that certain complex salts were found to be have proven sufficiently tolerable so that routine use on People could be considered for diagnostic purposes.

As the first representative of this class of substances, this has been in the European Patent application with publication number 71 564 described Dimegluminsalz of Gd DTPA (gadolinium III complex of diethylenetriaminepentaacetic acid) as Contrast agents for magnetic resonance imaging have so far been used in clinical trials Proven very well over 1000 patients.

This has become another representative of the complex salts in the German patent application 34 01 052 described meglumine salt of Gd DOTA (gadolinium III complex 1,4,7,10-tetraazacyclododecane-tetraacetic acid) for diagnostic Proven purposes.

The focus of the application of these complex salts is on diseases of the Central nervous system.

So far, however, there are no NMR diagnostics for the visualization of an increased Bone metabolism or calcification characteristic of certain diseases of soft tissues known, for example, for the early detection of Bone metastases, certain soft tissue tumors, heart attacks and strokes are suitable.

The invention is therefore based on the object, these compounds and means to provide, as well as a process for their manufacture and a to create suitable starting material. This object is achieved by the invention solved.  

It has been found that compounds resulting from the anion of a complex-forming Phosphonate and one or more central ions of an element of the atomic numbers 21 to 29, 31, 32, 38, 39 to 83 and optionally one or several cations of an inorganic and / or organic base or amino acid exist, surprisingly excellent for the production of NMR radio and X-ray diagnostics, especially for the early detection of heart attacks and strokes as well as for bone diseases. The compounds of the invention are described by the general formula I.

wherein

n the numbers 0, 1 or 2, m the numbers 0 or 1, R¹ and R² hydrogen atoms, lower alkyl groups, phenyl groups, benzyl groups or, if n stands for the number 0, together a trimethylene or a tetramethylene group, R³ is a hydrogen atom, a bromine atom, Fluorine atom, a hydroxyl, cyanide, phenyl or halophenyl group, R⁴ is a hydrogen atom or a PO₃Z¹Z² group, X is a hydrogen atom and / or a metal ion equivalent, Z¹ and Z² independently of one another are a C₁-C₆-alkyl radical and / or X,

A straight or branched chain, saturated or unsaturated, optionally interrupted by a cyclohexyl group, optionally by a cyanide, hydroxy, phenyl, halophenyl, benzyl, C₁-C₆ alkyl or C₁-C₆-O-alkyl group substituted C₁-C₁₀ alkylene group,

mean,
and if desired free acidic groups are salted with organic and / or inorganic bases.

Compounds of the general formula I where X is hydrogen are used as complexing agents and with at least two of the substituents X in the Meaning of a metal ion equivalent referred to as metal complexes.

The element of the above atomic number, which is the central ion of the physiologically tolerated complex salt forms, can be used for the intended purpose of the diagnostic agent of the invention, of course be radioactive.

Is the agent according to the invention for use in X-ray diagnostics the central ion must be determined by an element with a higher atomic number derived in order to achieve sufficient absorption of the X-rays. It it has been found that for this purpose diagnostic agents which are a physiological compatible complex salt with central ion of elements of atomic numbers contain between 21 to 29, 40 to 83, are suitable; these are for example the lanthanum (III) ion and the above-mentioned ions of the lanthanide series.

The agent according to the invention is intended for use in NMR diagnostics (see European patent application No. 71 564), the central ion of the Complex salt be paramagnetic. These are especially the two and trivalent ions of the elements of atomic numbers 21 to 29, 42, 44 and 57 to 70. Suitable ions are, for example, chromium (III) -, manganese (II) -, iron (II) -, Cobalt (II) -, nickel (II) -, copper (II) -, praseodymium (III) -, neodymium (III) -, Samarium (III) and ytterbium (III) ion. Because of their very strong magnetic Moments are particularly preferred the gadolinium (III) -, terbium (III) -, Dysprosium (III), holmium (III), erbium (III) and iron (III) ion.

For the use of the agents according to the invention in nuclear medicine Diagnostics, the central ion must be radioactive. For example, are suitable Radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, strontium, Technetium, indium, ytterbium, gadolinium, iridium and samarium.  

Examples of suitable alkylene groups A are methylene, ethylene, 4-bromophenylmethylene, propylene, butylene, pentylene, hexylene, 3-butenylene, Methylmethylene, cyclohexylene, 2,2-dimethylethylene, 4-chlorophenylmethylene, Methoxymethylene, cyclohexylene methylene, 1-methylpropylene, 1-hydroxymethyl 2-methylpropylene, decylene and octylene group called.

If not all acidic hydrogen atoms are substituted by the central ion , one, several or all remaining hydrogen atom (s) can be Cations of inorganic and / or organic bases or amino acids replaced be. Suitable inorganic cations are, for example, the lithium ion, the Potassium ion, the calcium ion and especially the sodium ion. Suitable cations 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 Ornithins.

The introduction of phosphonic acid groups for the preparation of the invention Complexing agent, d. H. of compounds of general formula I with X in the Significance of hydrogen occurs through partial conversion of carboxyl groups in amide phosphonate groups which - according to the desired end product - suitable tetra-, penta- or hexacarboxylic acids. For this process all synthesis possibilities known to the person skilled in the art are possible. A An example of this is the reaction of the anhydrides or esters of the general Formulas II, IV and V  

wherein
R¹ and R² and n have the meaning given above and R⁵ represents a C₁-C₆ alkyl radical, with aminophosphonic acids of the general formula III

wherein
A, R³, R⁴ and m have the meanings given above and the phosphonic acid group (s) and the functional groups which may be present in A and R³ are optionally protected.

Examples of suitable aminophosphonic acids are: Amino- (4-bromophenyl) methyl-, 1-aminohexylidene-di-, Amino-3-hydroxypropyl-di-, 1-amino-3-bromopropylidene-di-, 1-amino-3-butenyl-, 1-aminoethyl-, 2-aminomethylidene-di-, 4-amino-butyl-, 1-aminocyclohexyl-, 1-amino-2,2-dimethyl-propylidene-di-, 3-amino-1- (4-chlorophenyl) -2-cyanopropylidene-, 1-amino-2-fluoroethylidene-di, amino-cyclohexylmethyl-di-, 4-amino-1- hydroxybutylidene-di-, 1-amino-1,3-dimethylbutyl-, 1-amino-2-hydroxyethylidene di-, 2-amino-1-hydroxy-3-methylbutyl-, 1-amino-2- (4-hydroxy-phenyl) -ethyl-, 3-amino-1-hydroxypropylidene-di-, 2-amino-phenyl-, 1-amino-2-phenylethyl-, Amino-phenylethyl-, 1-aminodecylidene-di-, 2-amino-1-hydroxy-1-methyl-ethyl-, 3-aminooctyl, 2-amino-phenyl-ethyl-phosphonic acid.

The aminophosphonic acids of the general formula III can also be protected Form, especially as lower alkyl esters, for example as methyl, ethyl, Propyl and butyl esters. You then have the compounds of the invention of the general formula I with Z¹ and / or Z² in the meaning of a C₁-C₆ alkyl radical. The subsequent removal of these groups, if desired is problem-free and can be carried out by customary methods known to those skilled in the art respectively.  

The acid anhydrides of the general formula II can be prepared by known methods Methods take place, for example, according to that in US Pat. No. 3,660,388 or procedure described in DE-OS 16 95 050 with acetic anhydride in Pyridine. In certain cases, however, it is particularly advantageous to eliminate water with carbodiimides in a suitable solvent, such as Example dimethylformamide or dimethylacetamide to be carried out gently.

The preparation of a monoanhydride of the general formula IV is based on the example of the monoanhydride of diethylenetriaminepentaacetic acid monoethyl ester from the monoethyl ester DTPA (J. Pharm. Sci. 68, 1979, 194):

N³- (2,6-dioxomorpholinoethyl) -N⁶- (ethoxycarbonylmethyl) -3,6-diazaoct-andioic acid

A suspension of 21.1 g (50 mmol) of N³, N⁶-bis- (carboxymethyl) -N⁹- (ethoxycarbonylmethyl) - 3,6,9-triazaundecanedioic acid in 250 ml of acetic anhydride is left after adding 24.2 ml of pyridine, stir for three days at room temperature. Then sucks the precipitate is washed three times with 50 ml of acetic anhydride and then stir it with absolute diethyl ether for several hours. To Aspirate, wash with absolute diethyl ether and dry in vacuo at 40 ° C 18.0 g (= 89% of theory) of a white powder with a melting point are obtained 195-196 ° C.

Analysis (based on anhydrous substance):
C 47.64, H 6.25, N 10.42 (calc.);
C 47.54, H 6.30, N 10.22 (found).

The conversion of the acid anhydrides to the phosphonamides according to the invention is carried out carried out in the liquid phase. Suitable reaction media are, for example Water, dipolar aprotic solvents such as acetonitrile, N-methylpyrrolidone, Dimethylformamide, dimethylacetamide and the like or mixtures thereof. The Reaction temperatures are between approx. 0 ° C to 100 ° C, with temperatures of 20 ° C to 80 ° C are preferred. The response times are between 0.5 hours and 2 days, preferably between 1 hour and 36 hours.  

The esters of the general formula V are prepared in a known manner, e.g. B. according to the in R.A. Guilmette et al., J. Pharm. Sci. 68, 194 (1979) Method.

The aminolysis of the esters takes place in the liquid phase, e.g. B. in a suitable higher-boiling solvents such as dimethylformamide, dimethylacetamide or dimethyl sulfoxide. The reaction temperatures are around 20 ° C to 200 ° C, whereby Temperatures of 100 ° C to 180 ° C are preferred. The response times are between 2 hours and 2 days, with response times between 4 and 36 hours are preferred.

In addition, all methods known to the person skilled in the art for converting Carboxyl groups in amide groups for the synthesis of the complexing agents according to the invention of the general formula I, for example the method according to Krejcarek and Tucker, Biochem. Biophys. Res. Commun. 77, 581 (1977) mixed anhydrides.

The compounds of general formula I thus obtained with X in meaning of a hydrogen atom are complexing agents. They can be isolated and be cleaned or without isolation in metal complexes of the general formula I with at least two of the substituents X in the meaning of a metal ion equivalent be transferred.

The metal complexes according to the invention are prepared in the manner as it is disclosed in the patents EP 71 564, EP 1 30 934 and DE-OS 34 01 052 by using the metal oxide or a metal salt (e.g. that Nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 21 to 29, 31, 32, 38 to 83 in water and / or a lower alcohol (such as Methanol, ethanol or isopropanol) dissolves or suspended and with the solution or suspension of the equivalent amount of the complexing acid of the general Formula I reacted with X in the meaning of a hydrogen atom and then if desired, acidic hydrogen atoms present from acid groups by cations of inorganic and / or organic bases or amino acids substituted.  

The neutralization takes place with the help of inorganic bases (e.g. hydroxides, Carbonates or bicarbonates) of, for example, sodium, potassium or lithium and / or organic bases such as primary, secondary and tertiary amines such as ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine, and basic amino acids, such as lysine, Arginine and ornithine.

To produce the neutral complex compounds, for example, the acidic complex salts in aqueous solution or suspension as much as desired Add bases so that the neutral point is reached. The solution obtained can then concentrated to dryness in vacuo. It is often an advantage the neutral salts formed by adding water-miscible solvents, such as lower alcohols (methanol, ethanol, isopropanol etc.), lower ketones (acetone etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.) to precipitate and so easy to isolate and good to to obtain cleaning crystals. It has proven to be particularly advantageous proved the desired base already during the complex formation of the reaction mixture add and thereby save one procedural step.

If the acidic complex compounds contain several free acidic groups, it is often useful to produce neutral mixed salts that are both inorganic and also contain organic cations as counterions.

This can be done, for example, by adding the complexing acid to aqueous suspension or solution with the oxide or salt of the central ion supplying element and half of the amount required for neutralization an organic base, isolates the complex salt formed, if desired purified and then for complete neutralization with the required Amount of inorganic bases added. The order of base addition can can also be reversed.

In the case of using radioisotopes containing complex compounds their manufacture according to the volume I in "Radiotracers for Medical Applications" CRC-Press, Boca Raton, Florida.  

The diagnostic agents according to the invention are also produced in a manner known per se by using the complex compounds according to the invention optionally with the addition of the additives customary in galenics in aqueous Medium suspended or dissolved and then the suspension or solution if necessary sterilized. Suitable additives are, for example, physiological harmless buffers (such as tromethamine), small additions of complexing agents (such as diethylenetriamine-pentaacetic acid) or, if necessary, Electrolytes such as sodium chloride or, if necessary, antioxidants such as ascorbic acid or other stabilizers.

Are suspensions or solutions for enteral administration or other purposes of the agents according to the invention in water or physiological saline solution, they can be mixed with one or more auxiliary agents commonly used in galenics (e.g. methyl cellulose, lactose, mannitol) and / or surfactants (e.g. lecithins, Tweens®, Myrj® and / or flavorings for flavor correction (e.g. ethereal Oils).

In principle, it is also possible to use the diagnostic agents according to the invention can also be produced without isolating the complex salts. In any case, must be special Care should be taken to chelate so that the Salts and salt solutions according to the invention are practically free of non-complexed toxic metal ions.

This can be done, for example, with the help of color indicators such as xylenol orange Control titrations can be guaranteed during the manufacturing process. The The invention therefore also relates to processes for the preparation of the complex compounds and their salts. As a final security, cleaning of the isolated remains Complex salt.

Are suspensions of complex compounds for oral administration or other purposes in water or physiological saline, a sparingly soluble complex compound with one or more commonly used in galenics Excipients and / or surfactants and / or flavorings for flavor correction mixed.  

The diagnostic agents according to the invention preferably contain 1 .mu.mole to 1 mole per liter of the complex salt and are usually in amounts of 0.001 dosed up to 5 mmol / kg. They are for enteral and parenteral administration certainly.

The complex compounds according to the invention are used

• 1.) for NMR diagnostics in the form of their complexes with the ions of the elements with atomic numbers 21 to 29, 42, 44 and 57 to 70,
• 2.) for radio diagnostics in the form of their complexes with the radioisotopes of Elements with atomic numbers 27, 29, 31, 32, 38, 39, 43, 49, 62, 64, 70 and 77,
• 3.) for X-ray diagnostics in the form of their complexes with the ions of the elements of atomic numbers 40 to 83.

The agents according to the invention meet the diverse requirements for Suitability as a contrast medium for magnetic resonance imaging. So they are excellent suitable after oral or parenteral application by increasing the signal intensity in the image obtained with the aid of an MRI scanner to improve its informative value. Furthermore, they show the high effectiveness that is necessary to the body with the smallest possible amounts of foreign substances strain, and the good tolerance that is necessary to the non-invasive To maintain the character of the investigations (as described in J. Comput. Tomography 5, 6: 543-46 (1981), in Radiology 144, 343 (1982) and in Brevet Special de For example, Medicament No. 484 M (1960) compounds are too toxic).

Of the in the patents EP 71 564 and EP 1 30 934 and the German Patent application DE-OS 34 01 052 described compounds they differ especially because of their greater specificity for certain structures, pathological Processes, biochemical changes and metabolic processes. While the chelates mentioned above preferentially in the blood and in the extracellular space of the Distribute tissue evenly, that is to say nonspecifically, have the inventive Substances also have a high affinity for a few structures in the body. You will reach far higher concentrations there, the highlighting the relevant structures in the magnetic resonance tomogram, the scintigram or the computer tomogram is much clearer.  

As locally high concentrations are reached, the new substances can be dosed lower (for example in mg per body weight), which for the Magnetic resonance imaging and X-ray diagnostics with regard to tolerance is very desirable.

The good water solubility of the agents according to the invention allows highly concentrated Manufacture solutions so that the volume load of the circuit in keep reasonable limits and balance the dilution with body fluids, that means NMR diagnostics have to be 100 to 1000 times more water soluble than for NMR spectroscopy. Furthermore, the invention Not only a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of the toxic ions within the complexes that are not covalently bound within the time when the new contrast agents are completely excreted are done extremely slowly.

In general, the agents according to the invention for use as NMR diagnostics in amounts of 0.001 to 5 mmol / kg, preferably 0.005 to 0.5 doses of mmol / kg. Details of the application are, for example, in H.J. Weinmann et al., Am. J. of Roentgenology 142, 619 (1984).

The agents according to the invention are due to their favorable radioactive properties and the good stability of the complex compounds contained in them also suitable as radio diagnostics.

Details of their use and dosage are described, for example, in "Radiotraceres for Medical Applications ", CRS Press, Boca Raton, Florida.

For X-ray diagnostics, elements must have a sufficiently high atomic number in the substances according to the invention contain, are bound or complexed.

Because it is difficult to find sufficiently high concentrations for X-ray diagnostics To achieve the specific substances concerned is particularly important the use of sensitive methods such as computer tomography or energy-dependent subtraction methods.  

In general, the agents according to the invention are for use as X-ray contrast agents in analogy to, for example, meglumine diatrizoate in amounts of 0.1 to 5 mmol / kg, preferably 0.25 to 1 mmol / kg.

Details of the use of X-ray contrast media are, for example, in Barke, X-ray contrast media, G. Thieme, Leipzig (1970) and P. Thurn, E. Bücheler "Introduction to X-Ray Diagnostics", G. Thieme, Stuttgart, New York (1977) discussed.

Overall, new complexing agents, metal complexes and metal complex salts have been successfully achieved to synthesize the new opportunities in diagnostic and open up therapeutic medicine. Above all, the development of new types Imaging methods in medical diagnostics allow this development appear desirable.

The following examples serve to explain the subject matter of the invention.

Example 1 a) N³, N⁶-bis (carboxymethyl) -N⁹- [4,4-bis (dihydroxy-phosphoryl) -n-butylca-rbamoylmethyl] - 3,6,9-triazaundecanedioic acid

20.17 g (50 mmol) of N³- (2,6-dioxomorpholinoethyl) -N⁶- (ethoxycarbonylmethyl) - 3,6-diazaoctanedioic acid are dissolved in 500 ml of dimethylformamide. Then drips 25.3 g (250 mmol) of triethylamine at -5 ° C., then a solution of 17.27 g (50 mmol) 4-amino-butane-1,1-bis (diethyl phosphonate) according to DE-OS 32 25 469 (Schering AG), in 250 ml of dimethylformamide. You leave after two hours in an ice bath, then stir for 16 hours at room temperature and then evaporates the solution to dryness in vacuo. The residue is dissolved in methanol and purified by silica gel chromatography. After the methanol has been distilled off, 18 g of a resinous product are obtained Residue, which is dissolved in 250 ml of dimethylformamide. For this you drip 48 g (240 mmol) of trimethyl iodosilane and leaves overnight at room temperature stir. After adding 180 ml of water, the mixture is heated at 50 ° C. for 2 hours, after cooling to room temperature, the aqueous phase is separated off and concentrated in a vacuum to dryness. The residue is dissolved in 200 ml of methanol and purified by silica gel chromatography. After concentration of the methanolic 8.5 g (57% of theory) of a white powder are obtained with a solution decomposition point at 120 ° C.

Analysis (based on anhydrous substance)
C 35.53, H 5.63, N 9.21, P 10.18 (calc.);
C 35.70, H 5.85, N 9.10, P 10.37 (found).

b) Preparation of a solution for injection of the sodium salt of gadolinium III Complex of the N³, N⁶-bis (carboxymethyl) -N⁹- [4,4-bis (dihydroxyphosphoryl) -n- butylcarbamoylmethyl] -3,6,9-triazaundecanedioic acid

6.08 g (10 mmol) of the compound obtained under a) are dissolved in 100 ml of water dissolved per injection and with 2.47 g (5 mmol) of gadolinium III carbonate, Gd₂ (CO₃) ₃, transferred. The mixture is heated until the evolution of gas has ended 50 ° C, the solution is brought to pH 7.2 by adding 5N sodium hydroxide solution fills them into ampoules, which are then heat sterilized.  

Example 2 Preparation of the TC-99m complex of the N³, N⁶-bis (carboxymethyl) -N⁹- [4,4-bis- (dihydroxyphosphoryl) -n-butyl (carbamoylmethyl] -3,6,9-triazaundecanedioic acid

80 ml of a 1.25 molar sodium citrate solution are used to produce about 100 "kits" brought to pH 5.5 and by gassing with nitrogen from oxygen exempted. Then 100 mg of the complexing agent obtained according to Example 1 are added with stirring until a clear solution is obtained. To do this, under a further prepared solution of 10 mg tin II Chloride dihydrate per ml in 1 ml 0.1 N hydrochloric acid. Then you set a pH from 5 a, diluted with water per injectione to 100 ml and sterilized the Solution by ultrafiltration through a 0.2 µ filter after adding 10 mg of ascorbic acid as a stabilizer. The solution is then placed under sterile conditions filled in multivials and freeze-dried. For use on patients one of the multivials is mixed with 2 ml of a solution of Tc-99m a radioactivity of 15 millicuries per ml. To form the Tc-99m complex the multivial is placed in a boiling water bath after five minutes. After this The finished dosage form is available for cooling.

The patient dose for bone examinations is 15-20 mCi, for diagnosis a myocardial infarction 10-15 mCi.  

Example 3 a) N³, N⁶-bis (carboxymethyl) -N⁹- [3,3-bis (dihydroxyphosphoryl) -3-hydroxyp-ropyl- carbamoylmethyl] -3,6,9-triazaundecanedioic acid

2.35 g (10 mmol) of 3-amino-1-hydroxypropane-1,1-diphosphonic acid according to DE-OS 29 43 498, are suspended in 200 ml of water and mixed with 20 ml of 1-n Sodium hydroxide solution added to pH 9. Then, while keeping the pH constant Value 12.10 g (30 mmol) of N³- (2,6-dioxomorpholinoethyl) -N⁶- (ethoxycarbonylmethyl) - -3,6-diazaoctanedioic acid. After stirring overnight, bring the Solution to pH 12.5 and allowed to stir for another 3 hours. Then you bring with Amberlite® IR 120 to pH 7, filtered from the exchange resin and purifies the reaction product by silica gel chromatography (Eluent butanol / ammonia / ethanol / water).

The combined substance-containing eluates are evaporated to dryness in vacuo, the residue taken up in 50 ml of water and the solution with Amberlite® IR 120 treated. 1.3 g of a white powder of Melting point 145 ° C after concentration of the filtrate in vacuo to dryness.

Analysis (based on anhydrous substance)
C 33.45, H 5.28, N 9.18, P 10.15 (calc.);
C 33.56, H 5.50, N 9.30, P 10.02 (ger.).

b) Preparation of a solution for injection of the sodium salt of gadolinium III Complex of N³, N⁶-bis (carboxymethyl) -N⁹- [3,3-bis (dihydroxyphosphoryl) -3- hydroxypropylcarbamoylmethyl] -3,6,9-triazaundecanedioic acid

305.2 g (0.5 mol) of the compound obtained under a) are dissolved in 8.5 l of water pro injectione with the addition of 123.6 g (0.25 mol) of gadolinium III carbonate, Gd₂ (CO₃) ₃, dissolved at 50 ° C. After the gas evolution is finished under Fumigation with nitrogen brought to pH 7.2 with 5N sodium hydroxide solution. The solution for injection is made up to 10 l with water per injection and in ampoules filled, which are heat sterilized. Patient dose: 0.01 mmol / kg.  

Example 4 a) N³, N⁹-bis (2,2-dihydroxyphosphoryl) -ethylcarbamoylmethyl-N⁶-carboxyme-thyl- 3,6,9-triazaundecanedioic acid

12.50 g (100 mmol) of D, L-1-aminoethanephosphonic acid are dissolved in 500 ml of water dissolved at pH 9 with the addition of 2N sodium hydroxide solution. Then you give under constant of pH 17.9 g (50 mmol) 1,5-bis (2,6-dioxomorpholino) -3- Azapentane-3-acetic acid, prepared according to DE-OS 16 95 050, in portions. The mixture is left to stir overnight at room temperature and brought in with Amberlite® IR 120 to pH 1, filtered off the exchange resin and concentrated the filtrate in the Vacuum to dryness. 34 g of the tetrahydrate of the title compound are obtained as a white powder with a melting point of 140 ° C (with foaming).

Analysis (based on anhydrous substance)
C 35.59, H 5.81, N 11.53, P 10.20 (calc.);
C 35.61, H 5.93, N 11.50, P 10.35 (found).

b) Preparation of an injection solution of the sodium salt of the gadolinium III complex the N³, N⁹-bis (2,2-dihydroxyphosphoryl) -ethylcarbamoyl-N⁶-carboxymethyl- 3,6,9-triazaundecanedioic acid

60.7 g (0.1 mol) of the compound obtained under a) are in 8.5 l of water pro injectione with the addition of 24.72 g (0.05 mol) of gadolinium III carbonate Gd₂ (CO₃) ₃ dissolved at 50 ° C. After the gas evolution is finished under Fumigation with nitrogen brought to pH 7.2 with 5N sodium hydroxide solution. You fill up 10 l of water per injectione and fill the solution in ampoules be heat sterilized.  

Example 5 a) trans-1,2-diamino-N, N'-bis (carboxymethyl) -N, N'-bis [3,3-bis (dihydroxy-phosphoryl) - 3-hydroxypropylcarbamoylmethyl] cyclohexane

2.35 g (10 mol) of 3-amino-1-hydroxypropane-1-1-diphosphonic acid according to DE-OS 29 43 498, are suspended in 200 ml of water and mixed with 20 ml of 1N Sodium hydroxide solution added to pH 9. Then you give the constant pH 9.3 g (30 mmol) 4.4 ′ - (trans-1,2-tetramethylene ethylene) -bis- (2,6- morpholine dione), prepared according to DE-OS 33 24 236, in portions. To Stirring overnight at room temperature brings the solution to pH 7, filtered from the exchange resin and purifies the reaction product by chromatography on silica gel. The combined substance-containing eluates are in the Vacuum concentrated to dryness, the residue dissolved in ethanol and the filtered ethanolic solution over activated carbon. The filtrate dries up concentrated, the residue dissolved in 50 ml of water and the solution by adding acidified by Amberlite® IR 120. It sucks off the exchange resin and after concentration in vacuo to dryness, 1.5 g of a white powder is obtained from melting point 80-83 ° C.

Analysis (based on anhydrous substance)
C 30.78, H 5.17, N 7.18, P 15.87 (calc.);
C 30.55, H 5.30, N 7.25, P 15.63 (found).

b) Preparation of an injection solution of the sodium salt of the manganese-II complex of trans-1,2-diamino-N, N'-bis (carboxymethyl) -N, N'-bis [3,3-bis (dihydroxyphosphoryl) - 3-hydroxypropylcarbamoylmethyl] cyclohexane

78.04 (0.1 mol) of the compound obtained under a) are in 8.5 l of water pro injectione at 50 ° C with 11.5 g (0.1 mol) of manganese II carbonate, MnCO₃ stirred under nitrogen gas. After the end of carbon dioxide evolution brought to pH 6.8 with 5N sodium hydroxide solution and the solution is filled into ampoules which are heat sterilized.

Claims (15)

1. Physiologically compatible compounds of the general formula I wherein n is the number 0, 1 or 2, m is the number 0 or 1, R¹ and R² hydrogen atoms, lower alkyl groups, phenyl groups, benzyl groups or, if n stands for the number 0, together a trimethylene or a tetramethylene group, R³ is a hydrogen atom, a bromine atom , Fluorine atom, a hydroxyl, cyanide, phenyl or halophenyl group, R⁴ is a hydrogen atom or a PO₃Z¹Z² group, X is a hydrogen atom and / or a metal ion equivalent, Z¹ and Z² independently of one another are a C₁-C₆ alkyl radical and / or X, A straight or branched chain, saturated or unsaturated, optionally interrupted by a cyclohexyl group, optionally substituted by a cyanide, hydroxyl, phenyl, halophenyl, benzyl, C₁-C₆-alkyl or C₁-C₆-O-alkyl group C₁₀ alkylene group,
and their salts with organic and / or inorganic bases. 2. Physiologically compatible compounds according to claim 1, characterized characterized in that X represents hydrogen atoms. 3. Physiologically compatible compounds according to claim 1, characterized in that that at least two of the substituents X are metal ion equivalents at least one element of atomic numbers 21 to 29, 42, 44 or 57 to Are 70. 4. Physiologically compatible compounds according to claim 1, characterized in that that at least two of the substituents X are metal ion equivalents a radionuclide of at least one element of atomic numbers 27, 29, 31, 32, 38, 39, 43, 49, 62, 64, 70 or 77. 5. Physiologically compatible compounds according to claim 1, characterized in that that at least two of the substituents X are metal ion equivalents are at least one element of atomic numbers 40 to 83. 6. Physiologically compatible compounds according to claim 1, characterized in that that Y stands for a COOX group. 7. Physiologically compatible compounds according to claim 1, characterized in that Y for a stands. 8. Diagnostic agents containing at least one physiologically tolerable Compound according to Claims 1 to 6, optionally with those customary in galenics Additives. 9. Use of at least one physiologically compatible compound according to Claims 3, 5 and 6 for the preparation of agents for NMR diagnostics. 10. Use of at least one physiologically compatible compound according to Claims 4 to 6 for the production of agents for radio diagnostics.   11. Use of at least one physiologically compatible compound according to claims 5 to 7 for the preparation of agents for X-ray diagnostics. 12. A process for the preparation of physiologically compatible complex compounds of the general formula I according to claim 1, characterized in that in a manner known per se

• a) for the preparation of compounds of general formula I in which Y is a means
  a compound of the general formula II wherein
  R¹, R² and n have the meaning given above, with an aminophosphonate of the general formula III wherein
  A, R³, R⁴ and m have the meanings given above, the phosphonic acid group (s) and the functional groups which may be present in A and R³ being protected or reacted or
• b) for the preparation of compounds of general formula I in which Y represents a COOX group, a compound of general formula IV or V wherein
  R⁵ represents a C₁-C₆ alkyl radical and R¹, R² and n have the meanings given in Claim 1, with an aminophosphonate of the general formula III where the phosphonic acid group (s) and the functional groups which may be present in A and R³ are optionally protected,

releases the functional groups if necessary and the acids of general formula I thus obtained with X in meaning a hydrogen atom, if desired in a manner known per se, with at least a metal oxide or metal salt of an element of atomic numbers 21 to 29, 31, 32, 38 to 83 and then, if desired, existing acidic hydrogen atoms by cations of inorganic and / or organic bases or amino acids substituted. 13. A method for producing the diagnostic agent according to claim 7, characterized in that the in water or physiological Saline solution dissolved or suspended complex compound, optionally with the additives commonly used in galenics for enteral or parenteral Application brings appropriate form. 14. N³, N⁶-bis (carboxymethyl) -N⁹- [4,4-bis (dihydroxy-phosphoryl) -n-butylca-rbamoylmethyl] - 3,6,9-triazaundecanedioic acid,
Sodium salt of the gadolinium III complex of N³, N⁶-bis (carboxymethyl) -N⁹- [4,4-bis (dihydroxyphosphoryl) -n-butylcarbamoylmethyl] -3,6,9-triazaun-decanedioic acid,
Tc-99m complex of N³, N⁶-bis (carboxy-methyl) -N⁹- [4,4-bis (dihydroxy-phosphoryl) - n-butyl-carbamoylmethyl] -3,6,9-triazaundecanedioic acid,
N³, N⁶-bis (carboxymethyl) -N⁹- [3,3-bis (dihydroxyphosphoryl) -3-hydroxyp-ropylcarbamoylmethyl] -3,6,9-triazaundec andic acid,
Sodium salt of the gadolinium III complex of N³, N⁶-bis (carboxymethyl) -N⁹- [3,3-bis (dihydroxyphosphoryl) -3-hydroxy-propylcarbamoyl-methyl] -3,6, -9-triazaundecanedioic acid,
N³, N⁹-bis (2,2-dihydroxyphosphoryl) -ethylcarbamoylmethyl-N⁶-carboxymethyl-3,6,9-triazaundecanedioic acid,
Sodium salt of the gadolinium III complex of N³, N⁹-bis (2,2-dihydroxyphosphoryl) - ethylcarbamoylmethyl-N⁶-carboxymethyl-3,6,9-triazaundecanedioic acid,
Trans-1,2-diamino-N, N′-bis (carboxymethyl) -N, N′-bis [3,3-bis (dihydroxy-phosphoryl) -3-hydroxypropylcarbamoylmethyl] cyclohexane,
Sodium salt of the manganese-II complex of trans-1,2-diamino-N, N′-bis (carboxymethyl- (N, N′-bis [3,3-bis- (dihydroxyphosphoryl) -3-hydroxypropylcarbamoylmeth-yl] - cyclohexane.