SE510582C2 - Diagnostic agents containing at least one physiologically tolerable complex salt of the anion of a complexing acid - Google Patents

Abstract

Diagnostic compsns. contg. one or more complex salts (I) dissolved or suspended in an H2O-contg. medium are new, where (I) are salts of the anion of a complex-forming acid and one or more central ions of elements with atomic nos. of 21-29, 42, 44 or 57-83 and opt. one or more cations of inorganic and/or organic bases or amino acids. Complex salts of formula (Ia) are new (where X is COOY, PO3HY or CONHOY; A is CHR2CHR3, CH2CH2(ZCH2CH2)m, CH2CH(N(CH2X)2)CH2 or CH2CH2N(CH2CH2N(CH2X)2)CH2CH2; R1 is H or Me; R2 and R3 are H, lower alkyl, phenyl or benzyl, or R2+R3 is (CH2)3 or (CH2)4, or R2 is H and R3 is (CH2)p-C6H4-W-protein; p= 0 or 1; W is NH, NHCOCH2 or NHCS; m= 1-3; Z is O, S, NCH2X or NCH2CH2OR4; R4 is lower alkyl; V is as defined for X or is CH2OH, CONH(CH2)nX or COB, or V+V is (CH2)wN(CH2X)CH2CH2N(CH2X)(CH2)w when R1= R2= R3= H; B is a protein or lipid residue; n= 1-12; w= 1-3; with the proviso that there are 3-12 Y substituents, at least 2 being an equiv. of an ion of a metal with an atomic no. of 21-29, 32, 3 44 or 57-83 and at least one being a cation of an organic base or amino acid, any others being H or cations of an inorganic base). The compsns. may be used as NMR contrast agents for nuclear spin tomography, as X-ray contrast agents for radiography or as ultrasonic diagnostic agents.

Description

gsm ssz 2 Suitable complexing acids are those which are commonly used for complexing the above-mentioned central ions. Suitable complexing acids are, for example, methyl carbohydroxanoic acid groups, or in particular carboxymethylene groups, one and two of which are attached to a nitrogen atom, which supports the complex formation.

Suitable complex salts of the general formula I according to claim 1 are, for example, those of the general formula Ia CH -XX "CH 2 2 _ _ _ (Ia) N CHR2 CHR3 N / / \ cHR -v V-CHR1 1 wherein X , RI, R; and R; has the meaning specified in claim 1.

For the preparation of the complex salts of the general formula Ia, the following complex-forming acids are suitable, inter alia: the trans-1,2-cyclohexylenediaminetetraacetic acid and the 1,2-diphenylethylenediarine tetraacetic acid.

Suitable complex salts of the general formula I according to claim 1 are further those of the general formula Ib X "CH CH" X 2 \ N en / 2 '2 "CH2-v çHZ ç fl z (Ib) (cnziw (cnzlw // X-CH CH * X 2 2 3 510 582 wherein X and w have the meaning given in claim 1.

For the preparation of the complex salts of the general formula Ib, e.g. the following complexing acids: 1,4,8,11-tetraazacyclotetrade edge tetraacetic acid and isyric acid 1,4,7,10-tetraazacyclododekantetraacetic acid.

When not all acidic hydrogen atoms in the complexing acid are substituted with the central ion or ions, it is convenient to substitute the remaining hydrogen atoms with physiologically acceptable cations of inorganic and / or organic bases or amino acids due to the increase in the solubility of the complex salt. Suitable inorganic cations are, for example, the lithium ion, the potassium ion or in particular the nanium ion.

Suitable cations of organic bases include those of primary, secondary or tertiary amines such as ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine or in particular N-methylglucarine. Suitable cations of amino acids are, for example, those of lysine, arginine or ornithine.

The complexing acids required for the composition of the invention are known or can be prepared in a manner known per se.

The preparation of the complex salts is partly also known or can take place in a manner known per se by dissolving or suspending the metal oxide or a metal salt (eg the nitrate, chloride or sulphate) of the element with the numbers 21-29, 42, 44 or 58- 70 in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) and add with the solution or suspension the equivalent amount of the complexing acid in water and / or a lower alcohol and tube, if required under heating or heating to boiling point, until turnover is complete.

If the complex salt formed is insoluble in the solvent used, it is isolated by filtration. If it is soluble, it can be isolated by evaporating the solution to dryness, for example by spray drying. If there are additional acidic groups in the resulting complex salt, it is often convenient to transfer the acidic complex salt with inorganic and / or organic bases or amino acids, which form physiologically acceptable cations, to neutral complex salts and to isolate them. In many cases this is even indispensable, since the dissociation of the complex salt by the shift of the pH value to neutral is retained so much that in this way first the isolation of uniform products or at least their purification is made possible at all.

The preparation is suitably carried out with the aid of organic bases or basic amino acids. However, it may also be advantageous to carry out the neutralization with inorganic bases (hydroxides, carbonates or bicarbonates) of sodium, potassium or lithium.

For the preparation of the neutral salts, one can, for example, place the acidic complex salts in an aqueous solution or suspension with so much of the desired base that the neutral point is reached. The resulting solution can then be evaporated in vacuo to dryness. It is often advantageous to precipitate 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.) and thus obtain crystallisate, which is easy to insulate and purifies well. It has been found to be particularly advantageous to add the desired base to the reaction mixture already during the complex formation and thereby save a process step.

If the acidic complex salts contain fl your free acidic groups, it is often convenient to prepare neutral mixed salts, which contain both inorganic and organic physiologically acceptable cations as counterions. This can be done, for example, by reacting the complex-forming acid in the aqueous suspension or in solution with oxide or salt of the element giving the central ion, and half of the amount of an organic base required for the neutralization, isolating the complex salt formed, 510 582 it purifies if desired and then adds the required amount of inorganic base for complete neutralization. The effect of the base additive can also be reversed.

The diagnostic agents according to the invention are also prepared in a manner known per se by suspending or dissolving the complex salts, optionally while adding the additives customary in galenicium in aqueous medium, and then sterilizing the solution or suspension. Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine hydrochloride), minor additives of complexing agents (eg diethylenetriarnine pentaacetic acid) or, if necessary, electrolytes (eg sodium chloride).

In principle, it is also possible to prepare the diagnostic agents according to the invention without isolating the complex salts. In any case, special care must be taken so that the chelating is carried out so that the salts and salt solutions according to the invention are practically free of non-complexing toxic metal ions.

This can be achieved, for example, by means of color indicators such as xylene orange through control titration during the manufacturing process. The invention therefore also relates to processes for the preparation of the complex compounds and their salts. As a last resort, a purification of the isolated complex salt remains.

If, for the oral administration or other purpose, suspensions of the complex salts in water or physiological saline solution are desired, a less soluble complex salt is mixed with one or more of the auxiliaries and / or surfactants common in the galenic and / or flavoring agents.

The diagnostic agents according to the invention preferably contain 1 μmol to 1 mol per liter of the complex salt and are generally dosed in amounts of 0.001-5 mmol / kg.

They are intended for oral and especially parenteral use. 510 582 i 6 The agents according to the invention meet the many preconditions for compulsory education as a contrast agent for nuclear spin tomography. Thus, after excellent oral or parenteral administration, by increasing the signal intensity, they are excellently obliged to improve the reproducing power of the image obtained by means of nuclear spin tomographs.

Furthermore, they have the high effect required to load the body with the least possible amount of foreign substances, and the good tolerability, which is necessary to maintain the risk-free nature of the study (those in J.Comput. Tomography 261543 -46 (1981), the compounds listed in Radiology 1-4_4, 343 (1982) and in the French medical patent No. 484 M (1960) are, for example, too toxic). The good water solubility of the agents according to the invention allows the preparation of highly concentrated solutions so that the volume loading in the bloodstream is kept within tolerable limits and the dilution can be equalized with the body fluid, ie. NMR diagnostics must be 100-1000 times better water soluble than for NMR spectroscopy. Furthermore, according to the invention, the agents have not only a high stability in vitro but also a surprisingly high stability in vivo so that a release or an exchange of the non-covalently bound per se toxic ions in the complex only takes place very slowly within 24 hours within which - as pharmacological studies have shown - the new contrast media are completely excreted again.

In contrast to the conventional X-ray diagnostics with shadow X-ray contrast agents, in the NMR diagnostics with paramagnetic contrast agents there is no linear dependence on the signal amplification of the concentration used. As control studies show, an increase in the given dose does not necessarily lead to a signal amplification and at a higher dose of paramagnetic contraceptive unit, even the signal can be extinguished. For this reason, it was surprising that some pathological processes only became visible after administration of higher doses than those indicated in EP 71564 (which doses can range from 0.001 mmol / kg up to 5 mmol / kg) of a strong paramagnetic contrast agent according to the invention. For example, the detection of a defective blood-brain barrier in the area of a cranial abscess can only be performed after administration of 0.05-2.5 mmol / kg, preferably 0.1-1.5 mmol / kg of para-magnetic complex salts such as gadolinium-diethylenetriarinpentaacetic acid and manganese-1,2-cyclohexylenetriamine-tetraacetic acid in the form of their well water-soluble salts. For a dose greater than 0.1 mmol / kg, solutions of higher concentrations up to 1 mol / l, preferably 0.25-0.75 mol / l are required because only then the volume load is reduced and the handling of the injection solution is achieved.

In particular, lower dosages (below 1 mg / kg) and thus lower concentrated solutions (1 μmol / l to 5 mmol / l) than stated in EP 71564, are required for the organ-specific NMR diagnostics, for example for the detection of tumors. and heart attacks.

The following exemplary embodiments illustrate the invention in more detail.

Example 1 Sodium salt of the iron-III complex of trans-1,2-cyclohexylenedianian tetraacetic acid, C14H1 gFCNQOg. Na This compound is prepared analogously to the following recipe: 40 g (= 90 mmol) of diethylenetaxine pentaacetic acid are suspended in 100 ml of water and added with 24.3 g (= 90 mmol) of iron-III chloride hexahydrate (FeCl 3 ° 6 H 2 O) dissolved in 100 ml of water. The first dark blue suspension is heated to 95 ° C. After about 1 hour, the color turns light yellow. 270 ml of 1N sodium hydroxide solution are added to neutralize the hydrochloric acid formed and heat for a further 3 hours at 95 ° C. The resulting light yellow precipitate is filtered off with suction, washed with chloride and water and dried in vacuo at 60 ° C. 17.85 g (45% of theory) of a light yellow powder are obtained, the melting point of which is> 300 ° C. 17.85 g (= 40 mmol) of the resulting iron-IIl complex are suspended in 200 ml of water and added portionwise with 7.8 g (= 40 mmol) of N-methylglucamine, solid. It is heated for 5 hours for about 3 hours at 50 ° C and an almost clear, reddish-brown solution is obtained, which is filtered and then evaporated in vacuo to dryness. The residue is dried in vacuo at 50 ° C.

24.3 g (95% of theory) of a red-brown powder with a melting point of 131-133 ° C are obtained.

N-methylglucamine salt of the iron-III complex of trans-LZ-cyclohexylenediarine-N, N, N, N, -tC-phthalate / C21H36FCN3O13 2-Cyclohexylenediarine-N, N, N ', N'-tetraacetic acid, C21H36GdN3O13, 78 g (= 60 mmol) of trans-1,2-cyclohexylenediamine-N, N, N °, Nitetraacetic acid are suspended in 150 ml of water. After adding 1.7 g (= 60 mmol) of N-methylglucamine, an almost clear solution is obtained, to which is added 10.88 g (= 30 mmol) of gadolinium oxide (Gd2O3). The resuspended suspension is heated to 95 ° C for 6 hours. Filter off something undissolved and evaporate the filtrate to dryness. The residue is dried in vacuo at 60 ° C and pulverized. 38.6 g (92% of theory) of a white powder with a melting point of 258 DEG-261 DEG C. are obtained.

Analysis: (Ben) C 36.25 H 5.22 N 6.04 Gd 22.60 (Fun) C 36.40 H 5.50 N 5.98 Gd 22.52 Relaxivity (20 MHz, 39 ° C) T = 6.13 T; = 7.13 (L / mMol. Sec) LDSÛ (i.v., rat); about 2 mMol / kg 9 510 582 In the same way, with sodium hydroxide solution instead of the N-methyl-glucamine, the sodium salt of the gadolinimine-III complex of the trans-1,2-cyclohexylenediarine-N, N, N ', N' -tetraacetic acid is obtained. , cmHlgGdNgøg. Na.

Example 3 Preparation of the disodium salt of the manganese-II complex of trans-1,2-cyclohexylenedianine-N, N, N ', Nitetraacetic acid, C mHlglylnNzOg' 2 Na 34.6 g (= 100 mmol) trans-1.2 -cyclohexylenediamine-N, N, N °, N ”-tetraacetic acid is suspended under nitrogen in 100 ml of water and added with 11.5 g (= 100 mmol) of manganese II carbonate MnCO3. Heat to 95 ° C and add dropwise 200 ml of 1N sodium hydroxide solution. The clear solution is evaporated in vacuo and the residue is dried at 60 ° C in vacuo. 40.8 g (92% of theory) of a pink powder are obtained.

Analysis: (Calc.) C 37.94 H 4.09 N 6.32 Mn 12.40 (Fun) C 37.78 H 4.12 N 6.20 MnI2.31 Relaxivity (20 mHz, 39 ° C) T; = 2.94 T; = 5.03 (L / mMol.sec) LD50 (iv, rat): about 8 mMol / kg Correspondingly: from the copper I-II carbonate the disodium salt of the copper-II complex of trans-1,2- cyclohexylenediarine tetraacetic acid, cmHlgcllNgog. 2 Na, 510 582 in 10 of the cobalt-II carbonate disodium salt of the cobalt-II complex of trans-1,2-cyclohexylenediarine tetraacetic acid, C14H | gCON2O3 - 2 of the nickel-II-carbonate disodium salt of the nickel- The II complex of Iran-1,2-cyclohexylenediarriin tetraacetic acid, cmHlgNlNgøg. 2 Na.

With methylglucamine instead of sodium hydroxide solution are obtained: the di-N-methylglucarinine salt of the manganese-II complex of trans-LZ-cyclohexylenediamine tetraacetic acid, C Analysis (calculated on anhydrous substance) (Calc.) C 42.59 H 6.89 N 7.09 Mn 6.96 (Fun.) C 42.40 H 6.95 N 7.20 Mn 7.18 Relaxivity (20 MHx , 39 ° C) T, = 2.63 T; = 4.00 (L / mMol.sec) LDSO (iv rat): about 15 mMol / kg Example 4 The N-methylglucamine salt of the gadolinium-III complex of 1,2-diphenyleneethylenediamine tetraacetic acid, C29H3N3O : 29.2 g (= 100 mmol) of ethylenediarine-N, N, N ', N'-tetraacetic acid are suspended in 100 ml of water and heated with 18.1 g (= 50 mmol) of gadolinium-III-oxide, Gd2O3 to 95 ° C.

During the heating, 19.5 g (= 100 mmol) of N-methylglucamine are added portionwise.

After about 3 hours, a clear solution is obtained, which is filtered and evaporated in vacuo H 510 582 to dryness. The residue is dried in vacuo at 60 ° C. 61.3 g (95% of theory) of a white powder with an uncharacterized melting point are obtained.

Example 5 Preparation of the sodium salt of the gadolixilur-III complex of 1,4,7,10-tetraazacyclododecane-NN ", N", N '° etetraacetic acid, C16H24GdN4O3' Na 4.0 g (= 10 mmol) 1,4,7 , 10-Tetraazacyclododecane-NN ', N', N '° Ethraacetic acid is suspended in 20 ml of water and replaced with 10 ml of 1N sodium hydroxide solution. 1.8 g (= 5 mmol) of gadolinium-II-oxide, Gd2O3, are added and the suspension is heated for 2 hours at 50 ° C. The clear solution is filtered and evaporated in vacuo. The residue is dried and pulverized. 5 g (95% of theory) of a white powder are obtained.

Analysis: (Calc.) C 33.10 H 4.17 N 9.65 Gd 27.08 (Fun.) C 33.01 H 4.20 N 9.57 Gd 27.16 Relaxivity: (20 MHz, 39 ° c) T, = 1.73 T, = 2.16 (L / mMoisec) LDSO (iv, mouse): about 7.5 mMol / kg In the same way: N-methylglucamine salt of the gadolinimine-II1 complex of 1, 4,7,10- tetraazacyclododecane-NN ", N", N ° '° tetraacetic acid, C23H42GÖNSÛ13 510 582 12 Analysis (calculated on anhydrous substance) (Calc) c 36.64 H 5.62 N 9.29 (Fun. ) C 36.58 H 5.70 N 9.11 Gd 20.86 Gd 20.95 sodium salt of the gadolinium-III complex of 1,4,8,1,1-tetraazacyclotetradecane-NN ', N', N '° ethraacetic acid , C1gH2gGdN40g. Na.

Analysis (calculated on water fi in substance) (Calc.) C 35.52 H 4.64 N 9.20 Gd 25.89 (Fun) C 35.66 H 4.83 N 9.41 Gd 25.71 Example 6 Preparation of a solution of the N-methylglucarinine salt of the gadoliriiur-III complex of 1,4,7,10-tetraazacyclododecan tetraacetic acid 370.9 g (= 500 mmol) of the salt given in Example 11l is suspended in 500 ml of water for injection and dissolved by filling with water for injection to 1000 m1. The solution is filled into ampoules and sterilized for friends.

Example 7 Preparation of a solution of the di-N-methylglucamine salt of the manganese-II complex of trans-1,2-cyclohexylenediaminetetraacetic acid 395.9 g (= 500 mmol) of the salt given in Example 9 are suspended in 500 ml of water for injection. Add 1.3 g of ascorbic acid and bring to solution by filling with water for injection to 1000 ml. The solution is sterilized and filled into ampoules. Example 8 Preparation of a solution of the N-methylglucamine salt of the gadolyrimine-III complex of trans-1,2-cyclohexylenediaminetetraacetic acid 555.8 g (= 0.8 mol) of the salt described in Example 8 are dissolved in water for injection. to 1000 ml. After filtration over a pyrogen filter, the solution is filled into ampoules and heat sterilized.

Example 9 Preparation of a solution of the sodium salt of the gadolinium-III complex of trans-1,2-cyclohexylenediamine tetraacetic acid 558.6 (= 1 mol) of the salt mentioned in Example 8 is dissolved in water for injection to 1000 ml. in fl ashes and heat sterilized.

Example 10 Preparation of a solution of the N-methylglucamine salt of the gadolinium-III complex of 1,2-diphenylethylenediaminetetraacetic acid 396.9 g (= 500 mmol) of the salt described in Example 10 are suspended in 600 ml of water for injection and dissolved by filling into 1000 ml. The solution is filled into ampoules and sterilized. Example 1 I Preparation of a solution of the disodium salt of the manganese-II complex of trans-1,2-cyclohexylenediamine tetraacetic acid 44.3 g (= 100 mmol) of the salt mentioned in Example 9 are slurried under nitrogen. protection in 60 ml of water for injection and bring to solution by filling with water for injection to 100 ml. The solution is filled into ampoules and heat sterilized.

Example 12 Preparation of a solution of the sodium salt of the gadolinium-III complex of 1,4,8,1 1-tetraazacyclotetradecane-N, NN "" tetraacetic acid 552.6 g (= 1 mol) of the salt mentioned in Example 5 are dissolved in water for injection to 1000 rnl. The solution is filled into bottles and heat sterilized.

Claims (8)

New patents Use of at least one physiologically acceptable complex salt of the general formula X-CH CH -X 2 \ / 2 NAN v-crm1 / cnR -v wherein X represents the radicals -COOY, -PO3HY or -CONHOY , a metal ion equivalent and / or a physiologically acceptable cation of an inorganic or organic base or amino acid and wherein A represents the group -CHR 2 -CHR 9 - wherein R, represents hydrogen atoms or methyl groups, R; and R; together form a trimethylene group or a tetramethylene group or represent phenyl groups, benzyl groups, and V has the same meaning as X, or if R 1, R; and R; represents hydrogen atoms, both V are in common the group CH 2 X 2 H 2 X I - (cuz lw-N-cnz-cnz-N- (cH 2) w the substituents Y denote metal ion equivalents of an element having the order number 21-29, 42, 44 or 58-70 and optionally one or more physiologically with the additives customary in galenic dissolved or suspended in aqueous medium, for preparation of an in vivo NMR diagnostic agent. Use according to claim 1, wherein the complex salt consists of the di-N-methylglucamine salt of the manganese (II) complex of trans-1,2-cyclohexylenediarnetic acetic acid. Use according to claim 1, wherein the complex salt is the N-methylglucamine salt of the gadolinium UID complex of 1,4,7,10-tetraazacyclododecane tetraacetic acid. Use according to claim 1, wherein the complex salt consists of the disodium salt of the manganese UD complex of trans-1,2-cyclohexylene-diarrheal tetraacetic acid. Use according to claim 1, wherein the complex salt is the sodium salt of the gadolinium GID complex of 1,4,7,10-tetraazacyclododecane tetraacetic acid. Complex salts with the general formula 2 \ N 2 N-'AN V-CHR 1 / wherein X, A, V, R 1 and Y have the meaning given in claim 1 and at least two Y are a metal ion equivalent of an element with the order numbers 21- 29, 42, 44 or 58-70 and in addition at least one of the substituents Y is the physiologically acceptable cation of an organic base or amino acid. 17 510 582 Complex salt according to Claim 6, characterized in that it consists of di-N-methylglucamine salt of the manganese (II) complex of tri-1,2-cyclohexylene-tetraacetic acid. Complex salt according to Claim 6, characterized in that it consists of N-methylglucarinine salt of the gadolinium UID complex of 1,4,7,10-tetraazacyclododecane tetraacetic acid.