DK171097B1 - Metal complexes of di- and tri (carboxymethyl) tri and tetra (azabicycloalkane) derivatives and salts thereof, pharmaceutical agents containing these compounds, the use of the compounds for the preparation of agents for NMR X-ray or radio diagnostics or or radiation therapy as well as the method of preparing the compounds - Google Patents

Abstract

Macrocyclic compounds of the general formula I <IMAGE> in which @is a single or double bond, q is the numbers 0-5, A and B, which are identical or different, are each a straight-chain or branched alkylene group with 2 to 6 carbon atoms, D is a nitrogen, oxygen atom, the group =C=O, =NR<2> with R<2> being a hydrogen atom or a C1-C6-alkyl group, the group <IMAGE> with R<3> being a hydrogen or halogen atom, a phenyl, a C1-C6-alkyl group which is optionally substituted by one or more phenyl and/or hydroxyl group(s), being the radical OR<5> where R<5> is a C1-C6-alkyl radical which is optionally substituted by 1 to 3 hydroxyl groups, being the substituent <IMAGE> where l is the numbers 0 and 1 and R<6> and R<7> are, independently of one another, hydrogen atoms, the radical R<5>, phenyl or benzyl radicals which are optionally substituted by 1 to 3 hydroxyl groups, or R<6> and R<7> are, together with the nitrogen atom, a saturated or unsaturated, 5- or 6-membered ring which optionally contains another nitrogen, oxygen, sulphur atom or a carbonyl group and which is optionally substituted by 1 to 3 radicals R<5>, or one of the substituents R<6> or R<7> is the radical <IMAGE> or being the substituent G where G is a second macrocycle which is bonded via a direct bond, a bis(carbonylamino) group (-NH-CO-CO-NH-) or via a C1-C20-alkylene group which optionally carries at the ends carbonyl (> CO) or carbonylamino (-NH-CO-) groups or oxygen atoms and optionally contains one or more oxygen atom(s), Z-, acyl- or hydroxyacyl-substituted imino groups or one to two C-C double and/or C-C triple bonds, and has the general formula II <IMAGE> in which D<1> has the same meaning as D with the exception that D<1> does not contain the substituent G, or is the radical -CH-, =C- or -N- and F<1> has the same meaning as F with the exception that F<1> does not contain the substituent G, or is the radical -CH-, or =C-, E is a nitrogen, sulphur, oxygen atom, the <IMAGE> or >NR<4> group with R<4> being a hydroxyl group, being R<2> or being an optionally hydroxylated or carboxylated C1-C6-alkyl group, F is (-CHR<8>-)n or (=CR<8>)n with n being the numbers 0 or 1 and R<8> being R<1> or G, R<1> is a hydrogen or halogen atom or a C1-C6-alkyl group, Z is a hydrogen atom or the group -CH2COOY with Y being a hydrogen atom and/or a metal ion equivalent of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83, with the proviso that at least two of the substituents Z are the radical -CH2COOY and that the macrocyclic compound of the general formula I does not contain more than one radical G, and the salts thereof with inorganic and/or organic bases, amino acids or amino amides are valuable diagnostic and therapeutic agents.

Description

DK 171097 B1

The present invention relates to novel metal complexes of di- and tri (carboxymethyl) tri and tetra (azabi-cycloalkane) derivatives and salts thereof with the general formula I shown below, pharmaceutical agents containing at least one physiologically acceptable compound selected from the metal complexes of di- and tri (carboxymethyl) tri- and tetra (azabicycloalkane) derivatives of the general formula I according to claim 1 and 3,6,9,12,18-pentaazabicyclo [12.3.1] octadeca -1 (18), 14,16-triene-N-tetraacetic acid and 3,6,9,15-tetraazabicyclo [9.3.1] -10 pentadeca-1 (15), 11,13-triene-N-triacetic acid and their Cu, Pb, Co and Sr complexes, optionally together with the usual additives known from the galenic pharmacy, as well as the use of the compounds of formula I and the above-mentioned compounds for the preparation of agents for NMR, X-ray or radiopharmaceuticals. 15 diagnostics or for radio and radiotherapy. Furthermore, the invention relates to a process for preparing the novel compounds of formula I.

The above closely related compounds are known from the journal "Tetrahedron", Volume 37, pages 769-770, 1981. The 20 are compounds 3,6,9,12,18-pentaazabicyclo- [12.3.1] octadeca-1 (18 ), 14,16-triene-N-tetraacetic acid and 3,6,9,15-tetraazabicyclo [9.3.1] pentadeca-1 (15), 11,13-triene-N-triacetic acid and their Cu, Pb, Co and Sr complexes.

Metal complexes were already considered in the early 25 of the 1950s as contrast agents for radiology. However, the compounds used at the time were toxic in such a way that an application in humans was not considered. It was therefore quite surprising that certain complex salts subsequently proved to be tolerable to a sufficient extent to allow a routine use in humans for diagnostic purposes under consideration. As the first representative of this class of substances, the dimeglumine salt of Gd-DTPA (gadolinium-III complex 35 of diethylenetriamine pentaacetic acid) disclosed in published European Patent Application No. 71564 has so far been found to be highly suitable in clinical trials in over 7,000 2 DK 171097 B1 patients for use as a contrast agent for core pintomography. The center of gravity of the application lies in diseases of the central nervous system.

A major reason why Gd-DTPA can be tolerated so well in clinical use lies in the high efficacy of nuclear sphincter tomography, especially in many brain tumors. Because of its good effect, Gd-DTPA can be used at a much lower dose, namely 0.1 mmol / kg body weight, e.g. when used as an X-ray contrast agent in many X-ray examinations.

As a further representative of the complex salts, the meglumine salt of Gd-DOTA (gadolinium-III complex of 1,4,7,10-tetra-azacyclododecane-tetraacetic acid) disclosed in German Patent Application No. 34 01 052 has proved to be suitable for diagnostic purposes.

However, there is a desire to use chelates in higher doses as well. This is especially true for detection of certain diseases outside the central nervous system by nuclear spintomography (NMR diagnostics), but especially by the use of chelates as an X-ray contrast agent.

In order to keep the volume load of the body as low as possible, it is necessary to use highly concentrated chelate solutions. The previously known chelates are, in particular, on. because of their too high osmolality, less suitable thereto.

Thus, there is a need for chelates having a lower osmolality than the previously known chelates. At the same time, however, the conditions for the use of these compounds in humans must be met with respect to the distance between the effective dose and the toxic dose (the therapeutic width) detected by the animal experiment, the organ specificity, the stability, the contrast enhancing effect, the degree to which they tolerable, as well as the solubility of complex compounds. It is thus the object of the present invention to provide such compounds and agents as well as to provide as simple a method as possible for their preparation.

3 DK 171097 B1

This task is solved with the present invention.

The complex compounds of the invention and the solutions prepared therefrom fulfill the aforementioned requirements in a surprising way. They have a reduced osmolality as well as a more favorable therapeutic width and / or stability and storage capacity for the chemical constituents and / or organ specificity and / or contrast enhancing effect (e.g. relaxivity), and / or they are better tolerated (e.g. less cardiovascular or allergic side effects) than the diagnostics used so far.

Compounds which are closely related to the compounds of the invention of general formula I are known from EP Publication No. 232,751. These known compounds have the same useful effects as the compounds of the invention and can be used for NMR, X-ray or radio diagnostics or for radio or radiation therapy. However, the compounds of the invention have an effect which is surprisingly much better than the effect of the compounds known from the EP disclosure, in that they exhibit surprisingly high relaxivities compared to the known compounds.

Even without specific measures, the compounds allow pharmacokinetics to improve the diagnosis of numerous diseases. For the most part, the complexes are again excreted unchanged and rapidly, so that even in the case of relatively toxic metal ions, no harmful effects are observed despite a higher dosage.

The practical application of the new complexes and complexes is also facilitated by their favorable chemical stability.

»4 DK 171097 B1

A further significant advantage of the described complexes and complexing agents is their excellent chemical versatility. In addition to the central atom, the properties can be adapted to the demands in terms of efficacy, pharmacokinetics, tolerability, solubility, manageability, etc., in the choice of many different substituents in the 5 or 6 membered ring of the macrocycle and / or the salt generator. Thus, e.g. For example, a specificity desired by diagnostics and therapy is obtained for the compounds against structures in the organism, certain biochemical substances, metabolic processes, tissue states, or body fluids.

The invention thus relates to macrocyclic compounds which are characterized in that they have the general formula

Z-N N-Z

in 1 '' 'Νν-βγ z where 15. . .. is a single or double bond, A and B which are the same or different, each is a straight or branched alkylene group having 2 to 6 carbon atoms, D is one of the groups R3 R3

20 I I

-CH- or = C-, E is a nitrogen atom or an oxygen atom, F is (-CH2-) n or (= CH-) n, Z is a hydrogen atom or the group -CH2COOY, where Y is a hydrogen atom and / or a metal ion equivalent of an element DK 171097 B1 s having atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83, R3 is a hydrogen atom, a halogen atom or a group OR5 wherein R5 is a C 1 -C 6 alkyl group optionally substituted with 1-3 hydroxy groups and 5 n is 0 or 1, as well as their salts with inorganic and / or organic bases, amino acids or amino acid amides, provided that at least two of the substituents Z are for the group -CH2C00Y and that the general formula I does not represent 3,6,9,12,18-penta-10-azabicyclo [12.3.1] octadeca-1 (18), 14,16-triene-N-tetraacetic acid or 3,6,9,15-tetraazabicyclo [9.3.1] pentadeca-1 (15), 11,13-triene-N-triacetic acid or their Cu, Pb, Co and Sr complexes.

If n stands for the number 0 and the 5-ring 15 thus formed must be unsaturated, the double bond between the 5-ring positions is 2.3 and 4.5.

Compounds of general formula I wherein Y is a hydrogen atom are referred to as complexing agents and compounds wherein at least two of the substituents Y are a metal ion equivalent are referred to as metal complexes.

The element having the above atomic number forming the central ion of the physiologically tolerable complex salt can of course also be radioactive for the desired use of the diagnostic agent according to the invention.

If the agent of the invention is intended for use in NMR diagnostics, the central ion of the complex salt must be paramagnetic. These are particularly divalent and trivalent ions of elements with atomic numbers 21-29, 42, 44 and 58-70. Suitable ions are e.g. chromium (III), manganese (II), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III) and outer bium (III) ). Due to their very strong magnetic moment, the ions gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III) and iron (III) are particularly preferred.

For the use of the agent of the invention in nuclear medicine, the central ion must be radioactive. Suitable are e.g. radioactive isotopes of the elements copper, cobalt, 5 gallium, germanium, yttrium, strontium, technetium, indium, outer bium, gadolinium, samarium and iridium.

If the agent according to the invention is intended for use in X-ray diagnostics, the central ion must be derived from a higher atomic element element in order to obtain sufficient absorption of the X-rays. It has been found that for this purpose a diagnostic agent containing a physiologically acceptable complex salt with central ions of elements having atomic numbers 21-29, 42, 44 or 57-83 is suitable; these are e.g. the lanthanum (III) ion and the above 15 ions of the lanthanide series.

Halogen atoms include fluorine, chlorine, bromine and iodine.

As alkylene groups A and B, straight or branched chains having 2 to 6 carbon atoms, preferably ethylene, 20 methylethylene and propylene, are discussed.

When not all the acidic hydrogen atoms are substituted by the central ion, one, more or all of the remaining hydrogen atoms may be replaced by cations of inorganic and / or organic bases or amino acids. Suitable inorganic cations 25 are e.g. the lithium ion, potassium ion, calcium ion, magnesium ion and especially the sodium ion. Suitable cations of organic bases include those of primary, secondary or tertiary amines such as e.g. ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and especially N-30 methylglucamine. Suitable cations of amino acids are e.g. cations of lysine, arginine and ornithine.

7 DK 171097 B1

The preparation of the metal complexes according to the invention of the general formula I is carried out by alkylating compounds of the general formula I known per se.

η-n N-H

I / (D,

Off / i N-a i I f where X is

or a 5- or 6-membered ring which can be converted to the desired ring and wherein A and B have the above meanings, having a halogen compound of formula III

Al 2 CH 2 CO 2 '(III) s, where Hal is chlorine, bromine or iodine, and Y' is a hydrogen atom or an acidic cutting group, and then, optionally, after conversion of X to the 5- or 6 desired in the final product. -substituted ring and, where appropriate, after cleavage of the protecting group Y ', if desired, the complexes thus obtained of the general formula I wherein Y has the meaning of hydrogen react, in a manner known per se, with at least one metal oxide or metal salt of an element with atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83, whereupon, if desired, substituting acidic hydrogen atoms with cations of inorganic and / or organic bases, amino acids or amino acid amides, if desired.

As protecting groups Y 'come lower alkyl, aryl and aralkyl groups, e.g. eg methyl, ethyl, propyl, n-butyl, t-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis- (p-nitrophenyl) -methyl and trialkylsilyl groups in question. The cleavage of the protecting groups Y ', which can be carried out before or after conversion of X to the 5- or 6-membered ring desired in the final product, takes place according to methods known to those skilled in the art, e.g. by hydrolysis, hydrogenolysis, alkaline saponification of the ester with alkali in an aqueous-alcoholic solution at temperature ranges from 0 to 50 ° C or, in the case of e.g. t-butyl esters, using trifluoroacetic acid.

The alkylation of the adducts 1 'with the halogen compounds of general formula III takes place in polar aprotic solvents such as e.g. dimethylformamide, acetonitrile, dimethylsulfoxide, aqueous tetrahydrofuran or hexamethylphosphoric acid triamide in the presence of an acid binding agent such as e.g. a tertiary amine, e.g. triethylamine, trimethylamine, N, N-dimethylaminopyridine, 1,1-diazabicyclo [4,3,0] nonen-5 [DBN] 1,5-diazabicyclo [5,4,0] undecen-5 (DBU), an alkali metal , Alkaline earth metal carbonate, hydrogen carbonate or hydroxide (eg sodium, magnesium, barium or potassium carbonate, hydroxide or hydrogen carbonate) at temperatures between -10 ° C and 120 ° C, preferably between 0 ° C and 50 ° C. ° C.

The conversion of a precursor compound to the final product containing the desired 5- or 6-membered ring is accomplished by methods known to those skilled in the art. For example. should be mentioned hydrogenation of e.g. the rings pyridine [Advan. Catal. 14, 203 (1963)], pyrrole [M. Freifelder, Practical Catalytic

Hydrogenation, 577, Wiley-Interscience, New York-London-25 Sydney-Toronto 1971], furan [US Patent No. 3,194,818], pyrimidine [J. With. Chem. 23, 291 (1972)], deoxygenation of nitroxide [E. Klingsberg, The Chemistry of Heterocyclic Compounds, Volume 14, Part 2, Interscience Publishers New York, 9, 171017 B1, page 120 (1961)], transformation and introduction of functional groups into the 5- or 6-ring, e.g. liberation of phenolic hydroxy groups [J. Org. Chem. .53, 5, (1988)], introduction of halogen substituents [E. Klingsberg, The Chemistry of 5 Heterocyclic Compounds, Volume 14, Part 2, Interscience Publishers New York, page 341 (1961), Houben-Weyl, The Method of Organic Chemistry, Volume V / 3, 651 (1962)] or the exchange of heteroatoms, for example. conversion of a furan to a pyrrole (U.S. Patent No. 2,478,456).

The functionalization of 4-chloropyridine derivatives (e.g., azide exchange) by phase transfer methods using 18-crown-6 or tetrabutylammonium bromide as catalyst is described in "Phase Transfer Reactions" (Fluka Compendium volume 2; Walter E. Keller, Georg Thieme Verlag Stuttgart , New 15 York).

The subsequent removal of the protecting groups is problem-free and may e.g. is done by treatment with an acidic ion exchanger in aqueous-ethanolic solution.

10 DK 171097 B1

The synthesis of the adducts of general formula I 'to be alkylated takes place by cyclizing two reactants, one of which contains the substituent X, i. the desired 5 or 6 membered ring of the final product, or a precursor which can be converted into 5.

The cyclization is carried out by methods known in the literature (e.g., Org. Synth. 5J, 86 (1978), Macrocyclic Polyether Syntheses, Springer Verlag Berlin, Heidelberg, New York 1982, 10 Coord. Chem. Rev. 3.3 (1968) ), Ann. Chem. 197 6, 916; J. Org. Chem. 4_9, 110 [1984]); one of the two reactants carries at the chain end two leaving groups, the other two nitrogen atoms which nucleophilically displace these leaving groups. By way of example, the reaction of dichloro, dibromo, dimesyloxy, di -toxyloxy or di-1-oxycycarbonyl-1-alkylene compounds, which terminally contains the substituent X and optionally 1 to 5 nitrogen atoms, with only in diazalkylene compounds optionally containing 1 to 5 additional nitrogen atoms in the alkylene chain. Substituent X may instead also be contained in the second reactant, i. the one with terminated nucleophilic nitrogen atoms. The nitrogen atoms are optionally protected, e.g. as tosylates or trifluoroacetates and are released prior to the subsequent alkylation reaction by methods known in the literature (the tosylates, for example, with mineral acids, α1k1 imeta11 are in liquid ammonia, hydrobromic acid and phenol, RedAl®, 1ithium aluminum aluminum hydride, cf., for example, Liebigs Ann. Chem. 1977, 1344, Tetrahedron Letters 1976, 3477; the trifluoroacetates, for example, with mineral acids or ammonia in methanol, cf., for example, Tetrahedron Letters 1967, 30,289).

For the preparation of differently macrocycles substituted on the nitrogen atoms (hydrogen or the group CH 2 COOY), these atoms in the adducts may be provided with various protecting groups, e.g. with tosylate and benzyl groups. The latter is then also removed by methods known in the literature (preferably by hydration, e.g., EP Patent Application No. 232751).

If diester is used for about 1 hour in the case of the dyke compounds thus obtained, the methods thus obtained must be reduced by methods known to those skilled in the art, for example with diborane.

In addition, similarly substituted terminal bisaldehydes may be cyclized with the terminal terminals desired in the present case; the reduction of the Schiff bases thus obtained is accomplished by methods known in the literature, e.g. by catalytic hydrogenation [Helv. Chim. Acta 61, 1376 (1978)].

The preparation of the amines needed as starting compounds for the cyclization takes place by analogy with methods known in the literature.

15

Starting from an N-protected amino acid, a tri-amine is obtained by reaction with a partially protected diamine (for example, by the carbodiimide method), cleavage of the protecting group and diborane reduction.

20

Reaction of a diamine obtainable from amino acids (Eur. J.

With. Chem.-Chim. Ther. 2X> 333 (1986)) with the double molar amount of N-protected ω-amino acid gives a tetramine after a suitable work-up.

25

The desired diamines can also be prepared by Gabriel reduction from e.g. the corresponding tosylates or halides [cf. for example. Lnorg. Chem. 2jj, 4781 (1986)].

In either case, the number of carbon atoms between the N atoms can be determined by the nature of the diamines or amino acids used as coupling partners.

The compounds thus obtained of the general formula I, wherein each 35 y represents a hydrogen atom, form complexers. They can be isolated and purified or, without isolation, converted into metal complexes of the general formula 1 where at least two of the is substituents Y represent a metal ion equivalent.

12 DK 171097 B1

The metal complexes of the invention are prepared in the manner disclosed in DE Publication No. 34 01 052, by dissolving or suspending the metal oxide or metal salt (e.g., the nitrate, acetate, carbonate, chloride or sulfate) of a element with atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83 in water and / or in a lower alcohol (such as methanol, ethanol or isopropanol) and reacting the solution or suspension with the equivalent amount of a complexing acid of general formula I wherein 10 Y has the meaning of a hydrogen atom, preferably at temperatures between 40 and 100 ° C, and then, if desired, substituting acidic hydrogen atoms present on the acid groups with cations of inorganic and / or organic bases, amino acids or in the inocy of the.

15

The neutralization is done here by means of inorganic bases (e.g. hydroxides, carbonates or bicarbonates) of e.g. sodium, potassium, lithium, magnesium or calcium and / or organic base ^ including primary, secondary and tertiary amines such as e.g. ethanolamine, morpholine, glucamine, N-methyl and N, N-di methylglycine, as well as basic amino acids such as e.g. lysine, arginine and ornithine.

For the preparation of neutral complex compounds one can, for example, add to the acidic complex salts in aqueous solution or suspension so much of the desired bases that the neutral point is reached. The resulting solution can then be evaporated to dryness under vacuum. It is frequently an advantage to precipitate the neutral salts formed by the addition of water-miscible solvents, e.g. alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others) or polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane and others), thus obtaining crystalline 11 in easy-to-isolate easy to clean. It has been found to be particularly advantageous to add the desired base to the reaction mixture already during complex formation, thereby saving a method of measurement in n.

13 DK 171097 B1

If the acidic complex compounds contain several free acid groups, it is often convenient to prepare neutral mixture salts containing both inorganic and organic cations as well as counterions.

5

This can be done, for example. The reaction is carried out by reacting the complexing acid in aqueous suspension or solution with the oxide or salt of the element which provides the one ion and half of the required amount of neutralization of an organic base, after which the complex salt formed is isolated. the desired purifier and then adds the required amount of inorganic base for complete neutralization. The order of the base addition may also be the reverse.

If complex compounds containing radioactive isotopes are used, the preparation may be carried out according to the methods described in "Radiotracers for Medical Applications", Volume 1 CRC-Press, Boca Raton, Florida.

The preparation of the pharmaceutical composition according to the invention also takes place in a manner known per se, the complex compounds of the invention; optionally, with the addition of conventional additives from the galenic technique, the suspension or solution is suspended or dissolved in an aqueous medium, whereupon the suspension or solution is optionally sterilized. Suitable additives are e.g. physiologically acceptable buffers (such as t romethamine), minor additions of complexing agents (such as diethylenetriamine pentaacetic acid) or, if necessary, electrolytes such as sodium chloride or antioxidants such as e.g. ascorbic acid.

If, for the enteral administration or other purposes, suspensions or solutions of the agent of the invention are desired in water or in a physiological saline solution, these are admixed with one or more usual auxiliaries of the galenic technique (e.g., methyl cellulose, lactose, mannitol ) and / or surfactants (such as lecithin, Tween®, Myrj®) and / or flavoring flavoring agents (e.g., essential oils).

14 DK 171097 B1

In principle, it is also possible to prepare the pharmaceutical agents of the invention without isolating the complex salts. In each case care must be taken to conduct the chelate formation in such a way that the salts and salt solutions 5 of the invention are practically free of non-complexed, toxic-acting metal ions.

This can be done, for example. is realized by means of color indicators such as xylenol orange in control nitrates in batches during the manufacturing process. Thus, the invention also relates to processes for preparing the complex compounds and their salts. As a final safeguard, a cleansing of diet isolated complex salt can be done.

The pharmaceutical agents of the invention preferably contain 1 pmol - 1 mol / 1 complex salt and are usually dosed in amounts of 0.001 to 5 mmol / kg. They are intended for enteral and parenteral administration. The complex compounds of the invention come into use for NMR and X-ray diagnostics in the form of their complexes with elemental ions having atomic numbers 21-29, 42, 44 and 57-83; 2. for radio diagnostics and radiotherapy in the form of their complexes with radioactive isotopes of elements with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 and 77.

The compositions of the invention fulfill the many conditions for suitability as a contrast agent for core spintomography.

Thus, they are excellent at improving, after oral or parenteral administration, by increasing the signal intensity, the image obtained by nuclear spin tomographers with respect to the information obtainable with the image. In addition, they exhibit the high efficacy necessary for loading the body with as few amounts of foreign matter as possible and the good tolerability needed to maintain the non-invasive nature of the studies.

DK 171097 B1 15

The good water solubility and low osmolality of the compositions of the invention make it possible to prepare highly concentrated solutions by which the volume load of the circuit can be kept within reasonable limits and by which the dilution due to body fluids can be equalized, i.e. "NMR diagnostics" must be 100 to In addition, the agents of the invention exhibit not only a high stability in vitroy but also a surprisingly high stability in vivo, so that only a very slow release or exchange of the non-covalently bound - in themselves toxic - ions within the complexes within the time during which the new contrast agents are again completely excreted.

In general, the agents of the invention are dosed for use as NMR di agnostic in amounts of 0.001 to 5 mmol / kg, preferably 0.005 to 0.5 mmol / kg. Details of the use are mentioned e.g. in H. J. Weinmann et al., Am. J. of Roentgenology 142, 619 (1984).

Particularly low doses (less than 1 mg / kg body weight) of organ specific NMR di agnostic ia may e.g. used for detection of tumors and heart in nf arct.

Furthermore, the complex compounds of the invention can advantageously be used as susceptibility reagents and shift reagents to NMR spectroscopes in vivo.

The agents of the invention, because of their favorable properties and the good stability of the complex compounds contained therein, are also suitable as rad in od in agnost in ka. Details of the use and dosage are described e.g. in "Advised iotracers for Medical Applications", CRC-Press, Boca

Raton, Florida.

A further useful method with radioactive isotopes is the pos itron emission tomograph in which positron emitting isotopes such as e.g. ^^ Sc, ^ 4Sc, 82Fe, 55q0 0g 68q3 {w.

D. Heiss, Μ. E. Phelps, Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).

The compounds of the invention can also be used in radioimmune or radiation therapy. Such therapies differ only from the corresponding diagnostics by the amount and nature of the isotope used. The goal here is destruction of tumor cells by means of energy-rich short-wave radiation with as little range as possible. Suitable β-emitting ions are e.g. 46Sc, 47Sc, 48Sc, 72Ga and 73Ga. Suitable low emission α-emitting ions are e.g. ^ 11b i, 212Bi, 213b i and 2l ^ Bi, of which 212B i is preferred. A suitable proton and electron-emitting ion is l58Gd, obtainable from l57Gd by neutron capture 15 n in n g.

When using the therapeutic agents of the invention in vivo, these may be administered together with a suitable carrier, such as e.g. serum or a physiological saline solution, and together with another protein, such as e.g. human serum albumin. The dosage here depends on the nature of cellular destruction, the metal ion used and the nature of the bi-forming method.

The therapeutic agents of the invention are administered parenterally, preferably intravenously.

Details of the use of rad in therapist ika are mentioned e.g. in R. W. Kozak et al., TIBTEC. October 1986, 262.

The agents of the invention are excellent as X-ray contrast agent 1, where it should be particularly emphasized that with these no signs of the anaphylaxis-like reactions known from iodine-containing contrast agents can be recognized in biochemical pharmacological studies. They are particularly valuable because of the favorable absorption properties in areas of higher tube voltages for digital subtraction techniques.

In general, the agents of the invention are administered for use as an X-ray contrast agent in analogy with e.g. in quantities of 0.1 - 5 mmol / kg, preferably 0.25 - 1 mmol / kg.

5

Details of the use as an X-ray contrast agent are mentioned e.g. in Barke, Rontgenkontrastmittel, G. Thieme, Leipzig (1970) and P. Thurn, E. Biicheler - "EinfUhrung in die Rontgendiagnosik", G. Thieme, Stuttgart, New York (1977).

10

All in all, we have succeeded in synthesizing new complexes, metal complexes and metal complex salts, which open up new possibilities in the field of diagnostic and therapeutic medicine. In particular, the development of new bi-11 educational methods within 15 of medical diagnostics makes this development desirable.

The following examples serve to illustrate the present invention.

Example 1 a) 3,6,9-Tris- (p-tolylsulfonyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 1,2 3 4 5 6 7 8 9 10 11

To 121.9 g (200 moles) of N, N *, N "-tris- (p-tolylsulfonyl) diethyl-2-entriamine-N, N" -di sodium salt in 1600 ml of diformylamide is added dropwise in over 3 hours at 100 ° C a solution of 35.2 4 g (200 moles) of 2,6-bis (chloromethyl) pyrid in (dissolved in 700 ml of 5 methyl formamide). Stir overnight at 100 ° C. To the 6 hot solution is added dropwise 2 L of water and cooled to 70 ° C. The precipitate is aspirated and washed with water. After drying at 8, vacuum (60 ° C) is recrystallized from acetonitrile. 9 92.3 g (69% of theory) of the title compound are obtained as a colorless powder.

11

Analysis:

Calculated: C 57.46, H 5.43, N 8.38, 0 14.35, S 14.38 Found: C 57.39, H 5.48, N 8.35 S 14.34 18 DK 171097 B1 b) 3,6,9,15-tetraazibicyclo [9,3,1] pentadeca-1 (15), 11,13-tri-ene-tetrahydrosul fat 90.3 g (135 mmol) of the title of Example 1a The compound is introduced into 270 ml of concentrated sulfuric acid and stirred for 48 hours at 100 ° C. Cool to 0 ° C and drop by drop of 1.35 L of absolute ether. The precipitate is aspirated and stirred in 800 ml of methanol. After filtration and evaporation, it is dried under vacuum at 50 ° C.

10

Yield: 42.6 g (52.7% of theory) of an air-flowing solid.

Analysis: Calculated: C 22.07, H 4.38, N 9.36, 0 42.76, S 21.43 Found: C 22.10, H 4.42, N 9.31, S 21.40 c) 3,6,9,15-Tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 40.0 g (66.8 mmol) of the compound of the title of Example 1b are dissolved in 100 ml of water and adjusted with 32% sodium hydroxide to pH 11. Extract 8 times with 150 ml of methylene chloride and dry over magnesium sulfate. After evaporation under vacuum, 9.79 g (71% of theory) is obtained in the form of a yellow powder.

25

Analysis: Calculated: C 64.04, H 8.79, N 27.16

Found: C 63.91, H 8.85, N 26.98 d) 3,6,9-Tris- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadecane 1 (15), 11,13-triene 33.1 g (55.1 mmol) of the title compound of Example 1c are adjusted in 150 ml of water to pH 8.5 with 6N potassium hydroxide. To this solution is added 20.84 g (220.5 35 mmol) of chloroacetic acid, then adjusted to pH 9.5 with a 6N potassium hydroxide solution and heated to 45 ° C. Stir for 12 hours at this temperature and keep the pH between 9.5 and 10 upon addition of 6N potassium hydroxide. After cooling to room temperature, adjust to pH 2 with concentrated hydrochloric acid and evaporate to dryness. The residue is extracted with 300 ml of ethanol / 50 ml of acetone, the solid is removed and the filtrate is evaporated in vacuo. The residue is dissolved in a little water and put on a cation exchange column (IR 120). After rinsing with water, the ligand is eluted with a 0.5 N aqueous anmonia solution. The fractions are evaporated, taken up in a little water and passed over an ion exchange column (IRA 67). Wash with water first, then elute with 0.5 N formic acid. Evaporate under vacuum and dissolve the residue in warm ethanol. Upon careful addition of acetone and cooling in an ice bath, the title compound crystallizes.

Yield: 12.37 g (59% of theory) of a strongly hygroscopic compound.

Analysis: Calculated: C 53.67, H 6.36, N 14.73, 0.25.24 Found: C 53.55, H 6.43, N 14.65.

E) Gadolinium complex of 3,6,9-tris (carboxymethyl) - 3,6,9,15-tetraazabic cyclo [9,3,1] pentadeca-1 (15), 11,13-tr in a Dissolve 5.0 g (13.14 mmol) of the title compound of Example 1 in 20 ml of deionized water and add 2.38 g (6.57 mmol) of gado1 in nitric oxide. Stir for 3 hours at 90 ° C. The solution is filtered and the filtrate is freeze-dried.

30

Yield: 7.74 g (100% of theory) of a white amorphous powder, which according to analysis contains 9.31% water.

Calculated: C 38.19, H 3.96, N 10.46, 0 17.98, Gd 29.41 Found: C 38.11, H 4.05, N 10.38, Gd 29.32 DK 171097 B1 20

The following plasma relaxivity was measured (the measurements of re-laxate in onstage T ^ occurred in a Minispec p20 (Bruker) at 0.46 Tesla (= 2OMHz) at 40 ° C):

Ti-Reactivity: 7.64 (1 / mmol.sec) 5 For comparison: The di-meglumine salt of gadolini is uncomplexed by diethylenetriamine pentaacetic acid (Gd-DTPA): T ^ -relaxivity: 4.95 (1 / mmol.sec)

Osmolality of a 0.5 molar solution at 37 ° C: 0.55 (osml / kg water) 10 Total equivalents of dimeglumine salt of Gd-DTPA: 1.1 (osml / kg water).

Analogously, with iron III oxide, Fe 2 O 3, the iron III complex of 3,6,9-1ri s- (carboxymethyl) -3,6,9,15-tetraazabi-15 cyclone is obtained [9,3 , 1] pentadeca-1 (15), 11.13-1ri one as a brown powder.

Analysis (anhydrous):

Calculated: C 47.13, H 4.89, N 12.83, Fe 12.89

Found: C 47.04, H 4.96, N 12.84, Fe 12.81, Ti-reactivity (1 / mmol.sec), 40 ° C, water, 20 MHz: 0.49.

f) Dysprosium complex of 3,6, 9-1ri s- (carboxymethyl) - 3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene if instead of gado 1 in umox id in example le using dyspros ium oxide, the title compound is obtained practically in quantitative yield.

Calculated: C 37.82, H 3.92, N 10.38, 0.17.78, Dy 30.10

Found: C 37.87, H 3.98, N 10.24, Dy 30.02 35 21 g) Yterbium complex of 3,6,9-tris- (carboxymethyl) - 3,6,9, 15-tetraazabicyklo [9,3, l] pentadeca-l (15), ll, 13-triene

If, instead of gado1 in oxide in Example 1, 5 is used, outerbium oxide is obtained, the title compound is practically obtained in quantitative yield.

Analysis:

Calculated: C 37.09, H 3.85, N 10.18, 0 17.44, Yb 31.44 Found: C 37.13, H 3.94, N 10.09, Yb 31.37 h) Meglumine salt of the manganese-II complex of 3,6,9-tris- (carboxy-methyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), - 11,13- The triene 3.0 g (7.89 mmol) of the title compound of Example 1d is dissolved in 20 ml of deionized water and 907 mg (7.89 mmol) of manganese II carbonate are added. Stir for 2 hours at 80 ° C. The solution is filtered and the filtrate is adjusted to pH 7.2 with a 1 molar N-methylglucamine solution. Then freeze-dried.

Yield: 5.56 g (100% of theory) of a light pink, shiny, amorphous powder which, according to analysis, contains 12.2% of water.

Analysis:

Calculated: C 45.86, H 6.25, N 11.14, 0 28.00, Mn 8.74 Found: C 45.98, H 6.21, N 11.08, Mn 8.68 171097 B1

Example 2 a) 3,6,9-Tris- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadecane.

Dissolve 6.0 g (15.77 mmol) of the title compound of Example 1d in 200 ml of 5% hydrochloric acid and hydrogenate in an autoclave over a rhodium catalyst (5% Rh / C) at 30 bar and 45 ° C. After 4 hours, the catalyst is filtered off and 10 evaporated in vacuo. The residue is purified in the manner described in Example 1 on ion exchangers. Crystallization from methanol / acetone gives 4.75 g (78% of theory) of an extremely hygroscopic compound.

Analysis: Calculated: C 52.83, H 7.83, N 14.50, 0.24.84

Found: C 52.94, H 7.89, N 14.37.

b) Gadolinium complex of 3,6,9-tris- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadecane

To 4.3 g (11.13 mmol) of the title compound of Example 2a in 20 ml of ionized water are added 2.02 g (5.57 mmol) of sodium oxide and stirred at 90 ° C for 3 hours. The solution is filtered and the filtrate is freeze-dried. 6.5 g (100% of theory) of a white fluffy powder are obtained which, by analysis, contains 10.3% water.

Analysis:

Calculated: C 37.76, H 5.03, N 10.36, 0 17.76, Gd 29.08 Found: C 37.63, H 5.12, N 10.33, Gd 28.97.

35 23 DK 171097 B1

Example 3 a) 3,6,9-Tris- (acetyl) -3,6,9,15-tetraazabicyclo [9,3,1] penta-deca-1 (15), 11,13-triene 5 15,8 g (76.6 mmol) of the title compound of Example 1c, 42.7 ml of triethylamine (306.4 mmol) and 50 mg of dimethylaminopyridine (DMAP) are dissolved in 300 ml of absolute methylene chloride. 28.9 ml (306.4 mmol) of acetic anhydride are added and stirred overnight at room temperature. The solution is evaporated under vacuum and the residue is taken up in 200 ml of 3% sodium carbonate solution. Extract twice with 150 ml of methylene chloride. After drying the organic phase over magnesium sulfate, evaporate in vacuo. The residue is recrystallized from ether / ethyl acetate. 23.93 g (94% of theory) of the title compound are obtained in the form of white: flakes.

Analysis: Calculated: C 61.42, H 7.28, N 16.86, 0.14.44 Found: C 61.48, H 7.37, N 16.80 b) 3,6,9-Tris. (acetyl) -3,6,9,15-tetraazabicyclo [9,3,1] penta-deca-1 (15), 11,13-triene-15-N-oxide 1 2 3 4 5 6 22.5 g (67.7 mmol) of the compound given in Example 3a to 2 is dissolved in 100 ml of glacial acetic acid. 7.7 ml of a 30% hydrogen peroxide solution are added 7.7 ml and heated for 4 hours 4 to 70 ° C. Then an additional 3.9 ml of 30% hydrogen peroxide is added in dop 1 tablespoon in ng and stirred for an additional 1 hour at 70 ° C.

6

Evaporate in vacuo to one third in volume and gently add a second sodium carbonate solution until alkaline reaction. Extract twice with 250 ml of methylene chloride and then the organic phases are dried over magnesium sulfate. After evaporation under vacuum and crystallization from ether / ethyl acetate, 18.63 g (79% of theory) of the title compound is obtained in the form of a crystalline powder.

24 DK 171097 B1

Analysis: Calculated: C 58.60, H 6.94, N 16.08, 0 16.07 Found: C 58.47, H 6.88, N 16.14 c) 13-Nitro-3,6,9 -tris- (acetyl) -3,6,9,15-tetrazabic cyclo [9,3,1] pentadeca-1 (15), 11,13-triene-15-N-oxide 17 g (48) (8 mmol) of the title compound of Example 3b is dissolved in 40 ml of 90% sulfuric acid and heated to 60 ° C. To this solution is added dropwise 14 ml of concentrated nitric acid (d = 1,36) and stirred for 3 hours at 60 ° C.

It is poured on ice and the precipitate is filtered off and washed with plenty of water. After drying under vacuum, an orange powder is obtained which is recrystallized from acetone.

Yield: 9.2 g (48% of theory) in the form of yellow rhombus.

15

Analysis: Calculated: C 51.90, H 5.89, N 17.80, 0. 24.40 Found: C 52.01, H 5.76, N 17.64.

d) 13,13'-ethylenedioxy-bis- [3,6,9-tris- (acetyl) -3,6,9,15-tetrazabicyclo [9,3,1] pentadeca-1 (15), ll, 13-triene-15-N-oxide]

A freshly prepared solution of ethylene glycol disodium in dimethyl formamide (prepared from 620 mg ethanediol and 600 mg sodium hydride [80% suspension in paraffin oil] in 15 ml anhydrous dimethylformamide) is added dropwise to a 50 ° C hot solution over 8 minutes. g (20.34 mmol) of the title compound of Example 3c as shown below and stirred overnight at this temperature. Add 10 ml of water and evaporate in vacuo. The residue is chromatographed on silica gel (eluent: methanol / 32% aqueous ammonia solution = 10/1). After crystallization from ether / ethyl acetate, 3/15 g (41% of theory) of a yellowish crystalline powder is obtained.

Analysis: Calculated: C 57.28, H 6.68, N 14.85, 0.21.19 Found: C 57.40, H 6.61, N 14.79.

E) 13,13'-Ethylenedioxy-bis ~ [3,6,9-tris- (acetyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15) , 11,13-triene] 3 g (3.97 mmol) of the title compound of Example 3d are dissolved in 100 ml of ethanol, then 1 ml of concentrated hydrochloric acid is added and hydrogenated over Pd / C. The catalyst is filtered off and evaporated in vacuo and the residue is taken up in 50 ml of 3% sodium carbonate solution. Extract twice with 100 ml of methylene chloride. After drying the organic phases over magnesium sulfate, the solvent is separated off under vacuum and crystallized from ether / ethyl acetate.

Yield: 2.87 g (87% of theory) in the form of white flakes.

Analysis: Calculated: C 59.81, H 6.97, N 15.50, 0.17.71 Found: C 59.70, H 6.91, N 15.39 f) SiSlS'-ethylenedioxy-bis-tSjejBjlS pentadeca-1 (15), 11,13-triene] 2.5 g (3.46 mmol) of the title compound of Example 3e and 4.66 g (41.5 mmol) potassium t-butylate is dissolved in 40 ml of dioxane under nitrogen and heated overnight to reflux. Evaporate in vacuo, remove the residue in 50 ml of water and bring to pH 10 with 2N sodium hydroxide. After extraction 6 times with 80 ml of methylene chloride, each is dried over magnesium in sulfur 7 and the solvent removed under vacuum.

Yield: 1.55 g (95% of theory) of a pale yellow oil crystallizing on standing.

Analysis: Calculated: C 61.25, H 8.14, N 23.81, 0 6.80 Found: C 61.17, H 8.20, N 23.93 (g) 13.13 -ethylenedioxy-bis- [3,6,9-tris- (carboxymethyl) - 3,6,9,15-tetraazabic cyclo [9,3,1] pentadeca-1 (15), 11,13-triene] 5 Dissolve 1.4 g (2.97 mmol) of the title compound of Example 3f in 20 ml of water and add 2.25 g (23.8 mmol) of chloroacetic acid and then adjust the pH to 9.5 with 6 N potassium hydroxide. . Stir for 12 hours at 45 ° C and keep the pH between 9.5 and 10 by the addition of 6N potassium-1 ° hydroxide. Adjust to pH 2 with concentrated hydrochloric acid and purify on ion exchangers as described in Example 1d. Crystallization from ethanol / acetone gives 1.3 g (57% of theory) of the title compound as a strong hygroscopic solid.

15

Analysis: Calculated: C 52.80, H 6.16, N 13.69, 0.27.35 Found: C 52.67, H 6.07, N 13.75 h) Gadolinium complex of 13,13'-ethylene dioxide. bis- [3,6,9-tris- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca- 1 (15), 11,13-triene] 1.2 g ( 1.47 mmol) of the title compound of Example 3g is dissolved in 8 ml of deionized water and 533 mg (1.47 mmol) of sodium oxide are added. Stir for 3 hours at 90 ° C. The solution is filtered and the filtrate is freeze-dried.

Yield: 1.85 g (100% of theory) of an amorphous powder, which according to analysis contains 11.3% water.

30

Analysis: Calculated: C 38.45, H 3.93, N 9.94, 0.19.87, Gd 27.90 Found: C, 38.60, H, 3.98, N, 10.03, Gd, 27.79 27 DK 171097 B1

Example 4 a) 13-Ethynyl-3,6,9-tris- (acetyl) -3,6,9,15-tetraazabicyclo [9,1,1] pentadeca-1 (15), 11,13-triene-15N -oxide 5 10 g (25.42 mmol) of the title compound of Example 3c are dissolved in 200 ml of dimethoxyethane (DME) under nitrogen. Add 1.22 g (25.42 mmol) of sodium acetylid (18% suspension in xylene / light mineral oil) and stir overnight at room temperature. Add 10 ml of water and evaporate to dryness. The residue is chromatographed on silica gel (eluent: methanol / acetone = 1: 1). Crystallization from ether / ethyl acetate gives 5.02 g (53% of theory) of the title compound as a pale yellow powder.

15

Analysis: Calculated: C 61.27, H 6.49, N 15.05, 0.17.19 Found: C 61.31, H 6.55, N 14.94 b) 13.13 '- (1.3) -butadiyn-1,4-diyl) bis - ([3,6,9-tris- (acetyl) - 3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene-15N-oxide) 4.75 g (12.75 mmol) of the title compound of Example 3a are dissolved in 200 ml of pyridine and 2® 2.52 g (25, 5 mmol) copper-1-chloro id. The solution is saturated with oxygen and stirred for 2 days at room temperature.

It must be ensured below that an oxygen atmosphere is still maintained. After evaporation of the solution in vacuo, the residue is chromatographed on silica gel (eluent: 30 methano 1 / acetone = 1/2). Crystallization from a here / ethyl acetate gives 2.7 g o (57% of theory) of a slightly yellowish powder.

Analysis: Calculated: C 61.27, H 6.49, N 15.05, 0 17.19 Found: C 61.31, H 6.55, N 14.94 28 (c) 13.13 ( 1,3-butadiyn-1,4-di yl) -bi s- [3,6,9-tris- (acetyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 ( 15), 11, 13-triene] 2.5 g (3.37 mmol) of the title compound of Example 4b are dissolved in 50 ml of glacial acetic acid and heated to 60 ° C. Iron powder (1.88 g, 33.65 mmol) is added and stirred for 2 hours at 60 ° C. The solid is filtered off and the filtrate is evaporated to dryness. The residue is taken up in 100 ml of 3% sodium 10 carbonate solution and extracted 3 times with 100 ml of chloroform. After drying over magnesium sulfate, the solvent is removed in vacuo and crystallized from ether / acetone.

Yield: 2.08 g (87% of theory) in the form of a 1® colorless powder.

Analysis: Calculated: C 64.21, H6.52, N 15.77, 0.13.51 Found: C 64.31, H 6.60, N 15.68, d) 13.13 '- (1.3) -butadiyn-1,4-diyl) bis- [3,5,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene] 1.9 g (2 (67 mmol) of the title compound of Example 4c is dissolved in 20 ml of dioxane under nitrogen. Potassium t-butylate 2.4 g (21.38 mmol) is added and refluxed overnight. The solvent is removed under vacuum and the residue taken up in 20 ml of water. Adjust to pH 10 with 2N sodium hydroxide and extract 6 times with 60 ml of methylene chloride. After drying the organic phases 30 over magnesium sulfate, evaporate in vacuo.

Yield: 1.09 g (89% of theory) in the form of a pale yellow oil.

Analysis: Calculated: C 68.09, H 7.47, N 24.44 Found: C 68.18, H 7.54, N 24.51.

E) 13,13 '- (1,3-butadiyn-1,4-diyl) -bis- [3,6,9-tris- (carboxy-methyl) -3,6,9,15- tetraazabicyclo [9.3, 1] pentadeca-1 (15), 11,13-triene] 1.0 g (2.18 mmol) of the title compound of Example 4d is dissolved in 15 ml of water and there 1.65 g (17.44 mmol) of chloroacetic acid is added. Adjust to pH 9.5 with 6N potassium hydroxide and stir for 12 hours at 45 ° C. Below, the pH is maintained between 9.5 and 10 by the addition of 6N ka-10 l of aluminum hydroxide. After acidification with concentrated hydrochloric acid, purify as described in Example 1 on ion exchangers. Crystallization from methanol / acetone gives 1.07 g (61% of theory) of a strong hygroscopic solid.

Analysis: Calculated: C 56.57, H 5.75, N 13.89, 0.23.79 Found: C 56.64, H 5.81, N 13.79.

f) Gadolinium complex of 13,13 '- (1,3-butadiyn-1,4-diyl) bis- [3,6,9-tris- (carboxymethyl) -3,6,9,15-tetraazabicyclo [ 9.3, 1] pentadeca-1 (15), 11,13-triene] 900 mg (1.116 mmol) of the title compound of Example 4e is dissolved in 8 ml of water and 404 mg (1.116 mmol) of gadolinium oxide are added. . After stirring for 3 hours at 25 ° C, the solution is filtered and the filtrate is freeze-dried.

Yield: 1.35 g (100% of theory) in the form of a white amorphous powder, which according to analysis contains 8.9% water.

Calculated: C 40.92, H 3.62, N 10.05, 0 17.22, Gd 28.20 Found: C 40.81, H 3.65, N 10.18, Gd 28.11 35

Example 5 DK 171097 B1 a) 13-Chloro-3,6,9-tris- (acetyl) -3,6,9,15-tetraazabicyclo- [9.3.1] pentadeca-1 (15), 11,13- triene-15-N-oxide 5 7.3 g (18.56 mmol) of the title compound of Example 3c are heated in 50 ml of acetyl chloride for 4 hours to 50 ° C. Evaporate under vacuum and the residue is taken up in 200 ml of 3% sodium carbonate solution. Extract three times with 100 ml of chloroform and dry over magnesium sulfate. After removal of the solvent in vacuo, recrystallize from ether / ethyl acetate.

Yield: 6.18 g (87% of theory) in the form of a color dissolved crystalline powder.

15

Analysis:

Calcd: C 53.33, H 6.05, N 14.64, 0 16.72, Cl 9.26

Found: C 53.48, H 5.98, N 14.71, Cl 9.20 b) 13-Chloro-3,6,9-1ri s- (acetyl) -3,6,9,15-tetraazabi cyclo- [9.3.1] pentadeca-1 (15), 11,13-triene 6.0 g (15.67 mmol) of the title compound of Example 5a is dissolved in 300 ml of ethanol. Add 25 ml of concentrated hydrochloric acid and hydrogenate over Pd / C. After completion of hydrogen uptake, the catalyst is filtered off and evaporated under vacuum. The residue is taken up in 100 ml of 3% sodium carbonate solution and extracted twice with 100 ml of chloroform. The organic phases are dried over magnesium sulfate and evaporated under vacuum. Crystallization of the residue from ether / ethyl acetate gives 5.34 g (93% of theory) of the title compound as a colorless powder.

Analysis:

Calculated: C 55.66, H 6.32, N 15.27, 0 13.08, Cl 9.66

Found: C 55.57, H 6.38, N 15.31, Cl 9.59 DK 171097 B1 31 c) 13-Chloro-3,6,9,15-tetraazabicylo [9,3,1 l] pentadeca-1 (15), 11,13-triene 5.1 g (13.9 mmol) of the title compound of Example 5b is dissolved in 50 ml of dioxane under nitrogen. Potassium t-butyl 6.24 g (55.6 mmol) is added and refluxed overnight. Work up as described in Example 4d.

Yield: 3.01 g (9% of theory) of a light yellowish 1 ° oil which crystallizes after a short time.

Analysis: Calculated: C 54.88, H 7.12, N 23.28, Cl 14.73

Found: C 54.93, H 7.06, N 23.41, Cl 14.81 I5 d) 13-Chloro-3,6,9-1ri s- (carboxymethyl) -3,6,9,15-tetraazabi -cyclo [9.3, 1] pentadeca-1 (15), 11,13-triene 2.38 g (11.65 mmol) of the title compound of Example 5c is dissolved in 30 ml of water and 4 , 40 20 g (46.6 mmol) of chloroacetic acid. Adjust to pH 9.5 with 6N potassium hydroxide. Stir for 12 hours at 45 ° C and keep the pH between 9.5 and 10 by the addition of 6N potassium hydroxide. After working up as described in Example 1d and crystallization from methanol / acetone, 3.23 g (67% of theory) of the title compound are obtained as a solid which flows into air.

Analysis:

Calculated: C 49.22, H 5.59, N 13.51, O 23.14, Cl 8.55 Found: C 49.31, H 5.65, N 13.60, Cl 8.49 DK E) Gadolinium complex of 13-chloro-3,6,9-tris- (carboxymethyl) - 3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13- Dissolve 3.23 g (7.78 mmol) of the title compound of Example 5d in 20 ml of deionized water and add 1.41 g (3.89 mmol) of gadolinium oxide. Stir for 3 hours at 90 ° C. The solution is filtered and the filtrate is freeze-dried.

Yield: 4.9 g (100% of theory) of a white amorphous 1 ° powder, which according to analysis contains 11.9% water.

Analysis:

Calculated: C 35.88, H 3.54, N 9.85, 0 16.87, Cl 6.23, Gd 27.53

Found: C 35.94, H 3.57, N 10.01, Cl 6.17, Gd 27.56 -relaxivity (ax / mmol · sec), 40 ° C, water, 20 MHz: 5.44.

Example 6 a) 3,6,9,15-Tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-tri-ene-15-N-oxide 4.5 g (12.9 mmol ) of the title compound of Example 3b is dissolved in 40 ml of dioxane under nitrogen. 5.8 g (51.7 mmol) of potassium t-butylate are added and refluxed overnight. After working up as described in Example 3f, 2.61 g (91% of theory) of a pale yellow oil is obtained which crystallizes on standing.

Analysis: Calculated: C 59.43, H 8.16, N 25.20, 0 7.20 Found: C 59.37, H 8.21, N 25.13 33 DK 171097 B1 b) 3.6 9-Tris- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] -pentadeca-1 (15), 11,13-triene-15-N-oxide 2.4 g (10) Dissolve (77 mmol) of the title compound of Example 6a in 30 ml of water and add 4.1 g (43.4 mmol) of chloroacetic acid. Adjust to pH 9.5 with 6N potassium hydroxide. Stir for 12 hours at 45 ° C and maintain the pH between 9.5 and 10 by the addition of 6N potassium hydroxide. After working up as described in Example 1d, crystallization from ethanol / acetone gives 2.7 g (63% of theory) of a powerful hygroscopic powder.

Analysis·. Calculated: C, 51.51; H, 6.10; N, 14.14; 0.28.26 Found: C, 51.63; H, 6.01; N, 14.08; c) Gadolinium complex of 3,6,9-tris. (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene-15-N-oxy 2.1 g (5.3 mmol) of the title compound of Example 3b is dissolved in 15 ml of deionized water and 935 mg (2.65 mmol) of gadolinium oxide is added. Stir for 3 hours at 90 ° C. The solution is filtered and the filtrate is freeze-dried.

Yield: 3.2 g (100% of theory) of an amorphous powder, which according to analysis contains 10.7% water.

Analysis:

Calculated: C 37.08, H 3.84, N 10.18, 0 20.34, Gd 28.56 Found: C 37.18, H 3.79, N 10.21, Gd 28.48 34 DK 171097 B1

Example 7 a) 3,6,9-Tris- (p-tolylsulfonyl) -3,6,9-triaza-14-oxa-bicyclo- [9,2,1] tetradeca-1 (13), II-di and 5

To 121.9 g (200 mmol) of N, N ', N "-1ri s- (p-tolylsulphony 1) -diethylentriamine-N, N" disodium salt in 1600 ml of dimethylformamide is added dropwise at 100 ° C a solution of 33 g (200 mmol) 2,5-bi s- (chl ormethyl) -furan in 700 ml of di methylformamide over 1 ° 3 hours. Stir overnight at 100 ° C. To the warm-up solution is added dropwise 2 1 water. Cool to 0 ° C. The precipitate is washed with plenty of water and dried under vacuum (60 ° C). After crystallization from acetonitrile, 88.14 g (67% of theory) of a white powder is obtained.

15

Analysis: Calculated: C 56.60, H 5.36, N 6.39, 0 17.03, S 14.62 Found: C 56.52, H 5.42, N 6.30, S 14.60 b ) 3,6,9-Triaza-14-oxa-bicyclo [9.2, 1] tetradeca-1 (13), 11-diene 20 g (45.61 mmol) of the title compound of Example 7a are suspended. in 500 ml of liquid ammonia at -40 ° C. Then 10.49 g (456.1 mmol) of sodium / are added over 30 minutes and stirred for 3 hours at -40 ° C.

The excess sodium is destroyed by careful addition of ethanol (decolorization) and the ammonia is evaporated. The residue is taken up in 100 ml of water and adjusted to pH 11 with 6N sodium hydroxide. It is then extracted six times with 150 ml of methylene chloride and the organic phase is dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel (eluent: acetonitrile 1 / water / 3 2% ammonia solution = 10/3/1).

Yield: 3.95 g (45% of theory) as pale yellow oil.

Analysis: Calculated: C 61.51, H 8.78, N 21.52, 0. 8.19

Found: C 61.43, H 8.85, N 21.47 35 c) 3,6,9-Tris- (ethoxycarbonylmethyl) -3,6,9-triaza-14-oxa-bi-cyclo [9,2, l] tetradeca-l (13), ll-diene

To a mixture of 3.7 g (18.95 mmol) of the title compound of Example 5b and 6.03 g (56.85 mmol) of anhydrous sodium carbonate in 150 ml of dimethyl formamide is added dropwise at 50 ° C over 10 minutes. minutes 7 ml (62.5 mmol) of bromoacetic acid ethyl ester. Stir for 4 hours at 50 ° C. The solvent is removed in vacuo and the residue is stirred in 200 ml of methylene chloride. The solid is filtered off and the filtrate is evaporated. The residual oil is chromatographed on silica gel (eluent: methylene1 or id / ethano 1 = 12/1).

Yield: 6.1 g (71% of theory) of a slowly yellowing oil.

Analysis: Calculated: C 58.26, H 7.78, N 9.27, 0.24.69 Found: C 58.17, H 7.88, N 9.19 d) Gadolinium complex of 3.6.9- tri s- (carboxymethyl) -3,6,9-triaza-14-oxa-bicyclo [9.2, 1] tetradeca-1 (13), II-di and 5.0 g (11.02 mmol) of the The title compound of Example 7c is dissolved in 80 ml of ethanol and at 60 ° C is slowly added dropwise 36 ml of 1N sodium hydroxide. The mixture is heated to reflux for 30 minutes. It is evaporated to dryness and taken up in 20 ml of water and gently brought to pH 6.5 with 2N hydrochloric acid. After the addition of 2.0 g (5.57 mmol) of gadolinium oxide, the mixture is stirred at 90 ° C for 3 hours.

The solution is filtered and the filtrate is first passed over a short cation exchange column (IR-120) and then over a short anion exchange column (IRA-67). The eluate is freeze-dried.

Yield: 4.9 g (78% of theory) of an amorphous powder, which according to analysis contains 9.7% water.

Analysis: Calculated: C 36.70, H 3.85, N 8.03, 0.21.39, Gd 30.03

Found: C 36.51, H 3.81, N 8.11, Gd 29.91 36 DK 171097 B1

Example 8

Gadolinium complex of 3,6,9-tri s- (carboxymethyl) -3,6,9,14-tetra-traaza-bicyclo [9,2,1] tetradeca-1 (13), 11-diene 5 10.0 g (22.04 mmol) of the title compound of Example 7c is dissolved in 150 ml of ethanol and at 60 ° C 8 ml of 1N sodium hydroxide are added. Boil for one hour at reflux and then evaporate to dryness. The residue 10 is transferred to a shaking autoclave and 3.54 g (66.12 mmol) of ammonium chloride are added. After the addition of a vanadium oxide catalyst (U.S. Patent No. 2,478,456, Chem. Abstr.

44, 665 (1950)) condensed 100 ml of ammonia. Heat for 12 hours to 20 ° C. After evaporation of ammonia chromato-I5, the residue is graphed on silica gel (eluent1: dioxane / water / 32% aqueous ammonia solution = 6/2/1). Evaporation gives approx. 5.19 g (56% of theory) of the extremely hygroscopic ammonium salt, which is immediately reacted further. Dissolve in 25 ml of deionized water and adjust to pH 6.5 with 2N hydrochloric acid. 2.24 g (6.17 mmol) of sodium oxide are added and stirred for 3 hours at 90 ° C under nitrogen. 1 g of activated carbon is added and stirred for an additional hour at 90 ° C. The solution is filtered and the filtrate is first passed over a short cation exchange column (IR-120) and then over a short anion exchange column (IRA-67). The eluate is freeze-dried.

Yield: 6.0 g (47% of theory calculated from the title compound of Example 7c) in the form of an amorphous powder, which according to analysis contains 11.1% water. 1 35

Analysis:

Calculated: C 36.84, H 3.87, N 10.74, 0 18.40, Gd 30.15 Found: C 36.75, H 3.91, N 10.68, Gd 30.04 37 DK 171097 B1

Example 9 a) 15-Methoxy-3,6,9-tris- (p-tolylsulfonyl) -3,6,9-triaza-b-cyclo [9,3,1] pentadeca- (1 (15)) 11,13-triene 5 182.85 g (300 mmol) of N, N'N "-tris- (p-tolylsulfonyl) -diethylene-triamine in -N, N" -di sodium salt are dissolved in 2.4 L of Methylformamide and heated to 100 DEG C. A solution of 88.2 g (300 mmol) of 2,6-bi s- (bromomethyl) -1 ° phenol methyl ether in 11 liters of methylformamide is added dropwise over 3 hours. To the hot solution is added dropwise 3 L of water and cooled to 0 DEG C. The precipitate is washed with plenty of water and dried under vacuum (60 ° C). Crystallization from acetone-tril gives 119.3 g (57% of theory) of the compound mentioned in supra-l5 as a light cream powder.

Analysis: Calculated: C 58.51, H 5.63, N 6.02, 0 16.05, S 13.78 Found: C 58.41, H 5.68, N 6.13, S 13.70 b) 15-hydroxy-3,6,9-1-triazabic cyclo [9,3,1] pentadeca-1 (15), 11, -13-tr in a

To 100 g (143.3 mmol) of the title compound of Example 9a in 1 liter of dibutyl ether is gently added 21.75 g (573.2 mmol) of lithium aluminum hydride and heated to reflux overnight under reflux. Cool on ice bath / and excess lithium aluminum hydride is decomposed with ethanol and then with water. Evaporate to dryness, after which the residue is taken up in 1 1 2N sodium hydroxide and extracted 30 times with 200 ml of chloroform. After drying over magnesium sulfate, evaporate under vacuum / and the residue is chromatographed on silica gel (eluent: methanol / 32% aqueous ammonia cup solution = 10/1).

Yield: 8.56 g (27% of theory) of a yellowish oil.

Analysis: Calculated: C 65.13, H 8.65, N 18.99, 0 7.23

Found: C 65.18, H 8.60, N 19.10 35 DK 171097 B1 c) 15-Hydroxy-3,6,9-tris- (t-butoxycarbonylmethyl) -3,6,9-tri-azabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 8.3 g (37.5 mmol) of the title compound of Example 9b is dissolved in 250 ml of di-methyl formamide, and 15.55 g (112.5 mmol) of anhydrous potassium carbonate are added. To this, 16.3 ml (112.5 mmol) of bromoacetic acid t-butyl ester are added dropwise over 30 minutes and stirred overnight at room temperature. The solvent is evaporated to dryness and the residue is taken up in 300 ml of water and extracted 3 times with 150 ml of methylene chloride. The organic phases are dried over magnesium sulfate and evaporated under vacuum. The residual oil is chromatographed on silica gel (eluent1: methylene chloride / methanol = 15/1).

Yield: 13.32 g (63% of theory) of the title compound in the form of a colorless oil.

Analysis: Calculated: C 63.91, H 8.76, N 7.45, 0 19.87 Found: C 63.83, H 8.85, N 7.49 (d) 15-Hydroxy-3.6, 9-Tris- (carboxymethyl) -3,6,9-triazabicyclo [9.3, 1] pentadeca-1 (15), 11,13-triene 13.0 g (23.06 mmol) The title of Example 9c given compound is dissolved in 150 ml of trifluoroacetic acid and stirred overnight at room temperature. Evaporate under vacuum. The residue is taken up in a little water and purified with ion exchangers as described in Example 1d. Crystallization from methanol / acetone gives 6.5 g (71% of theory) of the title compound as an air-flowing powder.

Analysis: Calculated: C 54.67, H 6.37, N 10.63, 0.28.33

Found: C 54.51, H 6.30, N 10.57 35 DK 171097 B1 e) Gado1 aluminum comp 1 ex of 15-hydroxy-3,6,9-tris- (carboxymethyl-thyl) -3,6, 9-Triazabicyclo [9,3,1] pentadeca-1 (15), 11,13-tri en 4.0 g (10.1 mmol) of the title compound of Example 9d are dissolved in 25 ml of deionized water; and 1.84 g (5.05 mmol) of sodium oxide are added. Stir for 3 hours at 90 ° C, add 1 g of activated carbon and stir for a further 1 hour at this temperature. The solution is filtered and the filtrate is freeze-dried. 6.04 g (96% of theory) of an amorphous powder is obtained, which according to analysis contains 13.5% water.

Calculated: C 39.33, H 4.04, N 7.65, 0.20.38, Gd 28.61

Found: C 39.41, H 4.10, N 7.58, Gd 28.51

Example 10 a) 6-Benzyl-3,9-bis- (p-tolylsulfonyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13- triene

To 109.12 g (200 mmol) of N, N "-bi s- (p-two yl sulfonyl) -N'-benzyl-diethylenetriamine-N, N" disodium salt in 1500 ml of dimethylformamide is added dropwise at 100 ° C over 3 hours a solution of 35.2 g (200 mmol) of 2,6-bi s- (chl ormethyl) pyridine (dissolved in 700 ml of dimethylformamide). Stir overnight at 100 ° C. To the hot solution is added dropwise 2 L of water and cooled to 0 ° C. The precipitate is washed several times with water and dried under vacuum (60 ° C). Crystallization from acetonitrile 1 / ether gives 78.6 g (65% of theory) of a cream powder.

Analysis: Calculated: C 63.55, H 6.00, N 9.26, 0 10.58, S 10.60 Found: C 63.48, H 5.94, N 9.18, S 10.63 B) 6-Benzyl-3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene

To 75 g (124 mmol) of the title compound of Example 10a 5 in 1.5 liters of dibutyl ether is gently added 9.41 g (248 mmol) 1 in thi umal umi ni umhydr id ^ and heated to reflux overnight. over. After cooling in an ice bath, the excess lithium aluminum hydride is decomposed with ethanol and water. It is evaporated to dryness and taken up in 500 ml of 10 water and the pH is adjusted to 11 with 5N potassium hydroxide. It is extracted 6 times with 100 ml of chloroform, dried over magnesium sulfate and evaporated under vacuum. Chromatography on silica gel (eluent 1: ethanol / 32% aqueous ammonia solution = 12/1) gives 22.4 g (61% of theory) of a yellowish oil, IS which solidifies glassy.

Analysis: Calculated: C 72.94, H 8.16, N 18.90 Found: C 72.75, H 8.23, N 18.81 c) 6-Benzyl-3,9-bis- (ethoxycarbonylmethyl) 3,6,9,15-tetraaza-bicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 1

Analysis: Calculated: C, 66.64; H, 7.74; N, 11.96; 0.13.66

Found: C 66.51, H 7.81, N 11.88 35 g (33.74 mmol) of the title compound of Example 10b are dissolved in 300 ml of di methyl formamide. Into 1 -25 is added 7.13 g (67.48 mmol) of anhydrous sodium carbonate and heated to 50 ° C. Then, in 15 minutes, 8.3 ml (74.2 mmol) of bromoacetic acid ethyl ester are added dropwise; and stirring overnight at 50 ° C. The solvent is evaporated in vacuo and the residue is stirred twice in 350 ml of methylene chloride, filtered and evaporated. The residual oil is chromatographed on silica gel (eluent: methylene chloride / ethanol = 10/1).

Yield: 13.12 g (83% of theory) of the title compound as a colorless oil.

D) 3,9-bis- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-tri and 12 g (25) (6 mmol) of the title compound of Example 10c is dissolved in 100 ml of ethanol and heated to 60 ° C. To this solution, 32 ml of 2N sodium hydroxide is added dropwise and refluxed for 1 hour. Evaporate to dryness and dissolve the residue in 200 ml of 5% acetic acid. It is hydrogenated over Pd / C. Upon completion of hydrogen uptake, the catalyst is filtered off, then evaporated in vacuo and purified on ion exchangers as described in Example 1D. Crystallization from ethano 1 / acetone yields 6.52 g (79% of theory) of a strong hygroscopic solid.

I · 5 Analysis: Calculated: C 55.88, H 6.88, N 17.38, 0 19.85 Found: C 55.79, H 6.94, N 17.27 e) Manganese 11 complex of 3,9-bi s- (carboxymethyl) -3,6,9,15-theta-taazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 4 g (12.4 mmol) of the title compound of Example 10d is dissolved in 20 ml of deionized water and 1.43 g (12.4 mmol) of manganese (II) carbonate are added and heated for 2 hours to 80 ° C. The solution is first passed over a short cation exchange column (1R-120) and then over a short anion exchange column (IRA-67). The eluate is boiled with 1 g of activated carbon for 1 hour under reflux and then filtered. The filtrate is freeze-dried. Oer is obtained 4.4 g (87% of theory) of a light pink, slightly shiny, amorphous powder.

30

Analysis:

Calculated: C 48.00, H 5.37, N 14.93, 0 17.05, Mn 14.64

Found: C 47.93, H 5.41, N 14.87, Mn 14.58 35 42 DK 171097 B1

Example 11 a) 3,6-Bis- (p-tolylsulfonyl) -3,6,12-1r in azabicyclo [6,3,1] dodo-ca-1 (12), 8,10-triene 5

To 82.48 g (0.2 mole) of N, N'-bis (p-tolylsulfonyl) ethylenedia-m in n-di sodium salt in 1600 ml of dimethylformamide is added dropwise over a period of 3 hours at 100 ° C. 2 g (0.2 mole) of 2,6-bi s- (chloromethyl 1) -pyridine (dissolved in 700 ml of dimethylformamide). Stir overnight at 110 ° C. To the hot solution is added dropwise 2 L of water, after which the precipitate is sucked off and washed with plenty of water. After drying under vacuum (60 ° C), recrystallize from acetonitrile.

Yield: 67.9 g (72% of theory) of a cream 15 powder.

Analysis: Calculated: C 58.58, H 5.34, N 8.91, 0 13.57, S 13.60 Found: C 58.41, H 5.37, N 8.85, S 13.53 b) 3,6,12-triazabicyclo [6,3,1] dodeca-1 (12), 8,10-triene trihydrosulfate 67.0 g (142 mmol) of the compound of Example 11a are introduced in 200 ml of concentrated sulfuric acid and stir for 48 hours at 100 ° C. It is cooled to 0ο0, and then 1 L of absolute ether is added dropwise. The precipitate is aspirated and stirred in 600 ml of methanol. It is then filtered and evaporated to dryness. Drying under vacuum (60 ° C) gives 44.17 g (68% of theory) of the title compound in Form 3® of a crystalline solid.

Analysis: Calculated: C 23.63, H 4.19, N 9.19, 0 41.97, S 21.03

Found: C 23.57, H 4.24, N 9.11, S 20.96 43 DK 171097 B1 c) 3,6,12-Triazabicyclo [6.3.1] dodeca-1 (12), 8 , 10-triene

Dissolve 42.0 g (91.8 mmol) of the title compound of Example 11b in 100 ml of water and adjust to pH

5 11 with 32% sodium hydroxide. Extract 6 times with 200 ml of methylene chloride / and the combined phases are dried over magnesium sulfate. After evaporation under vacuum, 11.24 g (75% of theory) of a light yellow oil is obtained.

Analysis: Calculated: C 66.23, H 8.03, N 25.74 Found: C 66.17, H 8.09, N 25.67 d) 3,6-Bis- (carboxymethyl) -3,6 , 12-Triazabicyclo [6.3.1] dead-c a-1 (12), 8,10-triene 10 g (61.27 mmol) of the title compound of Example 11c are dissolved in 100 ml of water and 17.37 g (183.8 mmol) of chloroacetic acid are added. When adding 6N potassium hydroxide, adjust to pH 9.5 and heat to 20 45 ° C. Stir for 12 hours at this temperature, keeping the pH value with the addition of 6N potassium hydroxide between 9.5 and 10. It is cooled and purified on ion exchangers as described in Example 1d. Crystallization from ethanol / acetone gives 11.47 g (57% of theory) of the title compound as a crystalline solid.

Analysis: Calculated: C 55.90, H 6.14, N 15.05, 0.22.92 Found: C 55.81, H 6.19, N 14.94 e) Manganese complex of 3.6-bis- (carboxymethyl) -3,6,12-triazabi-cyclo [6,3,1] dodeca-1 (12), 8,10-triene 10.0 g (35.8 mmol) of the title compound, for example, is dissolved in 40 ml of deionized water and 4.12 g (35.8 mmol) of manganese slipper carbonate are added. Stir for 2 hours at 80 ° C. The solution is passed over a short anion exchange column and cation exchange column 1e and the eulate is stirred for 1 hour with 1 g of activated carbon at 80 ° C. Filter and freeze-dry the filtrate.

Yield: 12.7 g (96% of theory) of the title compound as an amorphous powder containing 11.3% water in a 1-5 g analysis.

Analysis:

Calculated: C 47.00, H 4.55, N 12.65, 0 19.26, Mn 16.54

Found: C 46.95, H 4.61, N 12.58, Mn 16.48

Example 12

Preparation of a solution of the gadolinium complex of 3,6,9-tris- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-1ri Dissolve 534.63 g (1 mole) of the compound described in Example 1c in 1200 ml of water for injection (pi). After addition of 24.62 g (50 mmol) of the monohydrate of the calcium trisodium salt 20 of DTPA, CaNa3DTPA, is filled with water p.i. to 2000 ml. Then, the solution is ultrafiltered, charged to ampoules and hot ester in 1 seres and ready for parenteral use.

Example 13

Preparation of a solution of the meglumine salt of the manganese (II) complex of 3,6,9-1ri s- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15) ), 11, 13-triene 34.92 g (50 mmol) of a compound described in Example 1h (water content 12.29%) is dissolved in 65 ml of water (pi). After addition of 492 mg (1 mmol) of the monohydrate of the calcium trisodium salt of DTPA, CaNa3DTPA, make up to 100 ml with water p.i.

The solution is then ultrafiltrated in 1, filled with ampoules and hot ester in 1 of the sera, and ready for parenteral use.

45 DK 171097 B1

Example 14

Composition of a powder for preparing a suspension for oral ndg in ft: 5,000 g of the gadolinium complex described in Example 1 3,895 g mannitol 0.100 g polyoxyethylene polyoxy propylene polymer 0.005 g flavors 10 8,000 g

Example 15

Preparation of a solution of the indium-III complex of 3,6,9-tris- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] -pentadecane

A solution of 100 µg of the compound described in Example 2a in 5 ml of a mixture of a 150 mmolar boiling salt and a 20 i mmo sodium acetate solution (pH 5.8) is added with a solution of 5 ml a nd in µm -111-chl or id in 1 ml of N-hydrochloric acid. By the addition of 0.1 N sodium hydroxide, the pH is brought to 7.2, the sterilized 1-liter solution is filled into 1 mt of ash and freeze-dried. The residue is taken up in a physiological saline solution and then forms a composition suitable for radiodiagnosis.

by analogy, a composition suitable for radiotherapy is obtained with y11rium-90-ch1 or id.

Example 16 a) 3,6,9-Tris- (p-tolylsulfonyl) -14-oxa-3,6,9-triazabicyclo- [9,2,1] tet radecan 1

To a solution of 28.19 g (64 mmol) of 2,5-bi s- (p-tosiloxymethyl) tetrahydrofuran in 500 ml of di-methylformamide is added dropwise over 2 hours at 100 ° C 39.01 g (64 mmol) Ν, Ν ', Ν "- B1 tri s- (p-tolylsulfonyl) diethylenetriam in nN, N" -di sodium salt dissolved in 210 ml of dimethyl formamide and stirred for 5 hours at 120 ° C. To the hot solution is added dropwise 700 ml of water and cooled to 0 ° C. The precipitate is aspirated, washed with water and dried under vacuum at 50 ° C. After recrystallized acetone ion, 33.5 g of the title compound is obtained in the form of a white powder, mp 175-178 * 0.

Lysis: Calculated: C 56.26, H 5.94, N 6.35, S 14.53 Found: C 56.01, H 5.99, N 6.28, 14.29 b) 14-Oxa. 3,6,9-Triazabicyclo [9.2, 1] tetradecane 30 g (45.3 mmol) of the title compound of Example 16a are introduced into 90 ml of concentrated sulfuric acid and stirred for 24 hours at 90 ° C. . Then cool to 0 * 0 and 350 ml of dry ether are added dropwise. The resulting precipitate is aspirated and dissolved in 50 ml of 40% sodium hydroxide and the solution is extracted 10 times with 50 ml of dichloromethane every 20 times. The organic phase is dried over magnesium sulfate and evaporated under vacuum. 6.23 g (69% of theory) of the title compound are obtained in the form of a white powder.

Analysis: Calculated: C 60.27, H 10.62, N 21.08 Found: C 60.04, H 10.75, N 20.95 c) 3,6,9-Tris- (carboxymethyl) -14 -oxa-3,6,9-triazabicyclo [9,1,1] tetradecane 30 Dissolve 6 g (30.1 mmol) of the title compound of Example 16b in 35 ml of water and add 11.38 g ( 120.4 mmol) chloride is dissolved in hydrochloric acid, after which this solution is adjusted to pH 9.5 with 6N potassium hydroxide. It is heated to 35 45 ° C for 12 hours, during which time the pH is kept in the range of 9.5 to 10 by the addition of additional potassium hydroxide. It is then cooled to room temperature and slowly concentrated hydrochloric acid is added up to pH 2 and evaporated under vacuum. The residue is dissolved in 100 ml of water and this solution is applied to a cation exchange column (IR 120). The column is first washed with plenty of water. The desired substance is then eluted with 0.5 N ammonia solution and evaporated, then the residue is dissolved in 100 ml of water and the solution is transferred to an anion exchange column (IRA 67).

Wash with water first and then elute with 0.5N formic acid. The acidic fractions are evaporated and the residue is dissolved in methanol. After the addition of acetone, the title compound crystallizes out (5.74 g, 51% of theory).

Analysis: Calculated: C 51.47, H 7.29, N 11.25 Found: C 51.60, H 7.21, N 11.38 d) Gadolinium complex of 3,6,9-tris- (carboxymethyl) ) -14-oxa-3,6,9-triazabicyclo [9.2, 1] tetradecane 3.73 g (10 mmol) of the title compound of Example 16c 2 ° is dissolved in 15 ml of water and stirred for 3 hours. with 1.81 g (5 mmol) of gadolinium oxide at 80 ° C. The solution obtained is filtered and stirred in order of first with 0.5 g of cation exchange (IR 120) and then with 0.5 g of anion exchanger (IRA 67), after which the solution is again filtered and subjected to freeze drying. 5.07 g (91% of theory) of the title compound is obtained as a white amorphous powder with a water content of 5.4%.

Analysis: Calculated: C 36.42, H 4.59, N 7.95, Gd 29.80 Found: C 36.30, H 4.61, N 7.82, Gd 29.59 (Corrected for water content) 35 48 DK 171097 B1

Example 17 a) 3,6,9-Tris- (p-tolylsulfonyl) -14-thia-3,6,9-triazabicyclo- [9,2,1] tetradeca-1 (13), 11-diene 60 97 g (100 mmol) of N, N ', N "-1ri s- (p-tolylsulfonyl) di-ethylene-triamine-N, N" -di sodium salt are dissolved in 800 ml of di methylformamide and added at 50 ° C dropwise over 90 minutes 19.9 g (110 mmol) of 2, 5-bi s-chlmethylmethylhiophene dissolved in 330 ml of dimethylformamide. Stir for an additional 90 minutes at 50 ° C, then dropwise add 1 L of water and the resulting precipitate is aspirated and washed with water. The residue is washed by; . 50 ° C in a vacuum drying cabinet and recrystallized from dioxane. 47.1 g (70% of theory) of the title compound are obtained in the form of a light yellow powder, mp 265-268 ° C. .

Analysis: Calculated: C 55.25, H 5.24, N 6.24, S 19.03 Found: C 55.38, H 5.44, N 6.10, S 19.01 20 b) 14-thia 3,6,9-triazabic cyclo [9.2, 1] tetradeca-1 (13), 11-diene

45 g (66.8 mmol) of the title compound of Example 17a are introduced into 130 ml of concentrated sulfuric acid and 25 stirred for 24 hours at 90-95 ° C. After cooling to 0 ° C

500 ml of ether are added dropwise, after which it is sucked and the precipitate is dissolved in 70 ml of 40% sodium hydroxide. The solution is extracted 5 times with 100 ml of dichloromethane each time, dried over magnesium sulfate and evaporated under vacuum. The residue is recrystallized from ether / hexane (3: 1) to give 7.8 g (55% of theory) of the title compound as a white powder.

Analysis: Calculated: C 56.83, H 8.11, N 19.88, S 15.17 Found: C 56.59, H 8.02, N 20.12, S 15.00 49 DK 171097 B1 c ) 3,6,9-tris- (carboxymethyl) -14-thia-3,6,9-triazabicyclo- [9.2, 1] tetradeca-1 (13), 11-diene 7.5 g (35.5 Dissolve in 45 ml of water and 13.42 g (142 mmol) of ch 1 is added in hydrochloric acid, after which the pH is adjusted to 9.5 with 6N potassium hydroxide. Thereafter, it is heated to 45-50 ° C for 12 hours, maintaining the pH of 9.5 to 10 during this time by adding additional potassium hydroxide. After cooling at -1 ° to 10 ° C, concentrated hydrochloric acid is added until pH 2.

The resulting precipitate is isolated by suction and dissolved in 100 ml of water and the solution is adsorbed on a cation exchange column (IR 120) * The column is washed with 2 L of water and then with 0.5 N ammonia solution. The ammonia fraction is evaporated under vacuum, the residue is dissolved in 100 ml of water and the solution is bound to an anion exchanger (IRA 67). The anion exchanger is eluted with water and 0.5N formic acid. From the acidic fractions, the title compound is obtained by evaporation under vacuum. For further purification, dissolve in methanol and t in 1 -20 add just as much acetone as to form a precipitate.

It is cooled to 0 ° C, the precipitate is aspirated and 7.7 g (56.3% of theory) of the title compound are obtained in the form of a light yellow powder.

Analysis: Calculated: C 49.86, H 6.01, N 10.90, S 8.32

Found: C 49.71, H 5.85, N 10.80, S 8.07 d) Gadolinium complex of 3,6,9-tris- (carboxymethyl) -14-thia-3,6,9-triazabicyclo [9 2,2 l] tetradeca-1 (13), 11-diene 30 g (5.19 mmol) of the title compound of Example 17c are heated together with 941 mg (2.60 mmol) of gadolinium oxide in 20 ml water for 4 hours to 85-90 ° C. The resulting solution is filtered and stirred with 0.26 g of cation exchange (IR 120) and 0.26 g of anion exchanger (IRA 67), filtered again and freeze dried. 2.66 g (95% of theory) of the title compound is obtained in the form of a white amorphous powder with a water content of 5.7%.

50 DK 171097 B1

Analysis: Calculated: C 35.61, H 3.74, Gd 29.14, N 7.79 S 5.94 Found: C 35.50, H 3.51, Gd 29.02, N 7.98, S 6.18 (The water content is taken into account in the calculation) Example 18 a) 13-Methoxy-3,6,9-tris- (p-tolylsulfonyl) -3,6,9,15-tetraaza-bicyclo [9, 3,1 l] pentadeca-1 (15), 11,13-triene 60.97 g (100 mmol) N, N ', N "-tris- (p-tolylsulfonyl) -diethylene-triamine-N, N" - The sodium salt is dissolved in 800 ml of dimethylformamide and dropwise added at 50 ° C over 90 minutes 47.76 g (100 mmol) of 2,6-bis- (p-tolylsulfonyloxymethyl) -4-methoxy-pyridine dissolved in 400 ml of di methylformamide. Stir for a further 5 hours at 90 ° C and add 1.1 L of water dropwise, then the resulting precipitate is aspirated and washed with water. The product is dried in a vacuum drying cabinet and recrystallized from isopropyl alcohol. 43.3 g (62% of theory) of the title compound are obtained in the form of a white powder.

20

Analysis: Calculated: C 56.71, H 5.48, N 8.016, S 13.76 Found: C 56.90, H 5.31, N 8.00, S 13.59 b) 13-Methoxy-3, 6,9,15-Tetraazabicyclo [9.3.1] pentadeca-1 (15), 11,13-triene 30 g (42.9 mmol) of the title compound of Example 18a are stirred with 100 ml of concentrated sulfuric acid for 24 hours at 95 ° C. After cooling to 0 ° C, 100 ml of ether are added dropwise to 100 ml, after which the precipitate formed is aspirated and dissolved in 60 ml of 40% sodium hydroxide. The solution is extracted 5 times with 75 ml of dichloromethane each time, dried over magnesium sulfate and evaporated under vacuum. The residue is recrystallized from diisopropyl ether to yield 6.59 g (65% of theory) of the title compound as a white powder.

Analysis: Calculated: C 60.99, H 8.53, N 23.71 Found: C 61.15, H 8.40, N 23.52 DK c) 13-Methoxy-3,6,9- tris- (carboxymethyl) -3,6,9,15-tetraazabi-cyclo [9,3,1] pentadeca-1 (15), 11,13-triene 6.2 g (26.2 mmol) of the title for example, 18b, dissolve in 40 ml of water and add 9.90 g (104.8 mmol) of chloroacetic acid. When 6N potassium hydroxide is added, the pH is adjusted to 9.5 and heated to 45-50 ° C for 8 hours. During this time, the pH of 9.5-10 is maintained by the addition of additional potassium hydroxide. It is cooled -1 ° afterwards in an ice bath and concentrated hydrochloric acid is added until a pH of 2. A precipitate is formed which is aspirated, the residue is dissolved under gentle heating in 80 ml of water and the solution is adsorbed on a cation exchange column (IR 120 ). Elute first with plenty of water and then with 0.5N ammonia solution. The basic eluate is collected and evaporated under vacuum. The residue is dissolved in 80 ml of water and the solution is adsorbed on an anion exchange column (IRA 67). First elute with water and then with 0.5N formic acid. The acidic fraction is evaporated in vacuo, the residue is dissolved in methanol and, with the addition of acetone, the title compound precipitates. 7.42 g (59% of theory) are obtained in the form of a white powder.

Analysis: Calculated: C 52.68, H 6.39, N 13.65

Found: C 52.81, H 6.22, N 13.80 d) Gado1ium complex of 13-methoxy-3,6,9-1ri s- (carboxymethyl) - 3,6,9,15-tetraazabicyclo [9 1,3] pentadeca-1 (15), 11,13-triene 5 g (12.18 mmol) of the title compound of Example 18c are heated with 2.21 g (6.09 mmol) of gadoli nine umoxy di 60 ml water for 4 hours to 85-90 ° C. The solution is filtered and freeze-dried. 6.74 g (98%) of the title compound is obtained in the form of a white amorphous powder with a water content of 4.1%.

Analysis: Calculated: C 38.29, H 4.10, Gd 27.85, N 9.92 Found: C 38.41, H 3.92, Gd 27.60, N 9.99 (Calculated height of water content) 35 52 DK 171097 B1

Example 19 a) 13-Chloro-3,6,9-tris- (t-butoxycarbonylmethyl) -3,6,9,15-tet-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13 -trien 5

To 7 g (29.08 mmol) of the title compound of Example 5c and 10.17 g (95.96 mmol) of sodium carbonate in 200 ml of acetonitrile are added 18.72 g (95.96 mmol) of bromoacetic acid t-butyl ester and stir for 24 hours at room temperature.

10

Evaporate in vacuo, remove the residue in 300 ml of water and extract 3 times with 200 ml of methylene chloride. After drying the organic phases over magnesium sulfate, evaporate in vacuo and the residual oil is chromatographed on silica gel (eluent: methylene or id / ethano 1 = 15/1).

Yield: 14.08 g (83% of theory) in the form of a color loose oil.

Analysis: Calculated: C 59.73, H 8.12, N 9.61, 0 16.46, Cl 6.08 Found: C 59.67, H 8.25, N 9.58, Cl 6.01 b) 13- (N-pyrrolidino) -3,6,9-tris- (t-butoxycarbonylmethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13 -triene 1

To 13.5 g (23.15 mmol) of the title compound of Example 19a, 3.94 g (46.3 mmol) of pyrrole id in non and 612 mg (2.32 mmol) of 18-krone-6 in Carefully add 200 ml of anhydrous di methyl formamide to 1.11 g (46.3 mmol) of sodium hydride (already washed with pentane). Stir for 72 hours at 70 ° C under nitrogen. The solution is cooled to room temperature and poured into 1.2 liters of ice water. Then extract 3 times with 250 ml of vinegar ester. The organic phase is dried over magnesium sulfate and evaporated under vacuum. The residue is chromatographed on silica gel (eluent1: methylene1 or id / metha no 1: 35/13).

Yield: 5.7 g (39% of theory) in the form of a colorless oil, which crystallized on standby.

DK 171097 B1 53

Analysis: Calculated: C 62.73, H 8.46, N 11.08, 0.17.73 Found: C 62.68, H 8.54, N 11.01 c) 13- (N-Pyrrolidino) -3 , 6,9-tris- (carboxymethyl) -3,6,9,15-tetrazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 5.1 g (8.07 Dissolve in 50 ml of trifluoroacetic acid and stir for 6 hours at room temperature. The solvent 10 is removed under vacuum and the zone described in Example 1d is purified on an exchange basis.

Crystallization from MeOH / acetone gives 2.88 g (77¾ of theory) of a strong hygroscopic substance.

15

Analysis: Calculated: C 54.42, H 6.31, N 15.11, 0.24.17 Found: C 54.37, H 6.42, N 15.05.

d) Gadolinium complex of 13- (N-pyrrolidin) -3,6,9-1ri s- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadecane 1 (15), 11, 13-triene 2.5 g (5.4 mmol) of the title compound of Example 19c are dissolved in 20 ml of one ounce in serified water and 978 mg (2.7) added mmol) gadolinium oxide. Stir for 3 hours at 90 ° C. The solution is filtered and the filtrate is freeze-dried.

Yield: 3.32 g (100% of theory) of an amorphous powder, which according to analysis contains 13.2% water.

30

Analysis:

Calculated: C 40.83, H 4.24, N 11.34, 0.18.13, Gd 25.46

Found: C 40.74, H 4.37, N 11.28, Gd 25.41 35 54 DK 171097 B1

Example 20 a) 13-Azido-3,6,9-tris- (t-butoxycarbonylmethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13 -triine 5 21 g (36.01 mmol) of the title compound of Example 19a are dissolved in 200 ml of dimethylformamide and 7.02 g (108 mmol) of sodium azide and 951 mg (3.6 mmol) of 18-krone are added. 6th Stir for 48 hours at 90 ° C.

10

After cooling to room temperature, pour into 1.5 l of ice water and extract three times with 200 ml of vinegar ester. After drying the organic phase over magnesium sulfate, evaporate and the residual oil is chromatographed on silica gel (eluent: methylene chloride or id / ethano1 = 15/1).

Yield: 10.83 g (51% of theory) in the form of a pale yellow oil.

Analysis: Calculated: C 59.06, H 8.03, N 16.63, 0 16.28 Found: C 59.17, H 8.05, N 16.51 b) 13-Amino-3.6, 9-Tris- (t-butoxycarbonylmethyl) -3,6,9,15-tetra-traazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 1 2 3 4 5 6

Analysis: Calculated: C 61.78, H 8.76, N 12.42, 0 17.03 Found: C 61.67, H 8.91, N 12.35 10 g (16.96 mmol) of the Dissolve in 400 ml of ethanol under the heading of Example 20a and 2, and add 1 3 g of Pearlman catalyst (20% palladium hydroxide on coal). After 4 hydrogenation for 24 hours at normal pressure, the catalyst is aspirated and evaporated under vacuum. The residual oil 6 is chromatographed on silica gel (eluent: methylene chloride / methanol / triethylamine = 10/1 / 0.05). 8.89 g (93% of theory) of a light yellow oil is obtained.

C) 13-amino-3,6,9-tris- (carboxymethyl) -3,6,9,15-tetrazabicyclo [9,3,1] pentadeca-1 (15), 11,13 The tri-8.2 g (14.55 mmol) of the compound of Example 20b 5 is dissolved in 100 ml of trifluoroacetic acid and stirred for 6 hours at room temperature. After evaporation of the solvent in vacuo, the residue is dissolved in 100 ml of water and transferred to a column filled with poly- (4-vinylpyridine). After evaporation under vacuum and crystallization from methanol / acetone, 5.24 g (91% of theory) is obtained in the form of a strong hygroscopic solid.

Analysis: Calculated: C 51.64, H 6.37, N 17.51, 0.24.28 Found: C 51.74, H 6.31, N 17.63 15 d) Gado1 aluminum complex of 13-amino-3 , 6,9-tri s- (carboxymethyl) - 3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 4.8 g (12,14 mmol) of the title compound of Example 20c is dissolved in 35 ml of ionized water and 2.2 g (6.07 mmol) of gadium oxide are added. The mixture is stirred at 90 ° C for 3 hours and the pH is kept at 5.5 by the addition of acetic acid. The solution is filtered and passed over a column filled with poly- (4-vinylpyridine). After treatment with activated charcoal, re-filter and freeze-dry.

Yield: 6.07 g (91% of theory) of an amorphous powder, which according to analysis contains 12.1% water.

Calculated: C 37.15, H 4.06, N 12.74, 0.17.47, Gd 28.61

Found: C 37.08, H 4.17, N 12.68, Gd 28.54

Example 21 56 a) 13- (Hydroxyacetamido) -3,6,9-tris- (t-butoxycarbonylmethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 ( 15), 11.5-trien 5.8 g (10.28 mmol) of the title compound of Example 20b, 861 mg (11.31 mmol) glycolic acid and 1.53 g (11.32 mmol) 1 -hydroxy-1H-benzotriazole hydrate is dissolved in 20 ml of 10 absolute di methyl formamide and cooled to 0 ° C. 2.36 g (11.32 mmol) of di-cyclohexylcarbodiem are added and stirred for 1 hour at 0 ° C; then overnight at room temperature. The solution is poured into 150 ml of ice water and extracted three times with 150 ml of vinegar ester. After drying the organic phase over magisium sulfate, evaporate in vacuo. The residue is chromatographed on silica gel (eluent: methylene1 or id / methano1 = 10/1).

Yield: 2.88 g (45¾ of theory) in the form of a color dissolved solid.

20

Analysis: Calculated: C 59.88, H 8.27, N 11.26, 0 20.59 Found: C 59.76, H 8.35, N 11.31 b) 13- (hydroxyacetamido) -3.6 , 9-Tri s- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 2.7 g (4.34 mmol) of the title compound of Example 21a is dissolved in 40 ml of trifluoroacetic acid and stirred for 6 hours at room temperature. Evaporate under vacuum and purify the residue as described in Example 1 on an exchange.

Crystallization from isopropanol gives 1.56 g (79% of theory) of a white powder.

Analysis: Calculated: C 50.32, H 6.00, N 15.45, 0.28.23

Found: C 50.24, H 6.07, N 15.49 57 57 171797 B1 c) Gadolinium complex of 13- (hydroxyacetamido) -3,6,9-tris- (carboxymethyl) -3,6,9,15 tetraazabicyclo [9.3.1] pentade-ca-1 (15), 11,13-triene 5 1.45 g (3.2 mmol) of the title compound of Example 21b is dissolved in 10 ml of deionized water and 580 mg (1.6 mmol) of sodium oxide are added. Stir for 3 hours at 90 ° C. The solution is filtered and the filtrate is freeze-dried.

Yield: 1.94 g (100% of theory) of an amorphous powder, which according to analysis contains 11.5% water.

Analysis:

Calculated: C 37.55, H 3.98, N 11.53, 0.21.06, Gd 25.88 Found: C 37.48, H 4.11, N 11.48, Gd 25.79

Example 22 a) 13-Chloro-3,6,9-tris- (p-tolylsulfonyl) -3,6,9-triazabicyclo [9,3,1] pentadeca-1 (15), 11,13- triene 182.85 g (300 mmol) of N, N ', N "-1ri s- (p-tosylsulfonyl 1) -diethylene-triamine-N, N" -di sodium saline are dissolved in 2.4 liters of methylformamide and heated to 100 ° C. To this, a solution of 63.15 g (300 mmol) of 4-chloro-2,6-bis (chloromethyl) pyridine in dimethyl formamide is added dropwise over 3 25 hours. Stir overnight at 100 ° C.

To the still hot solution is added dropwise 3 L of water and 30 are cooled to room temperature. The precipitate is washed in plenty of water and dried under vacuum (60 ° C). Crystallization from acetone-tril gives 128.7 g (51% of theory) of the title compound as a colorless powder.

Analysis:

Calculated: C 54.65, H 5.02, N 7.97, 0 13.65, S 13.68, Cl 5.04

Found: C 54.61, H 5.13, N 7.91, S 13.65, Cl 5.09 58 DK 171097 B1 b) 13- (N-morpholino) -3,6,9-tris- (p -tolylsulfonyl) -3,6,9-triazabic cyclo [9,3,1] pentadeca-1 (15), 11,13-triene 126 g (179 mmol) of the title mentioned in Example 22a Dissolve the compound in 500 ml of dimethyl sulfoxide and add 87.12 g (1 mole) of morpholine. The solution is stirred in an autoclave for 48 hours at 140 ° C and 10 bar. Cool, ° 9 is poured into 3 L of ice water and then the precipitate is suctioned. After drying under vacuum at 60 ° C, acetone is recrystallized. 87.72 g (65% of theory) of 10.72 are obtained in the form of a cream powder.

Analysis:

Calculated: C 57.35, H 5.75, N 9.29, 0 14.86, S 12.76 Found: C 57.32, H 5.84, N 9.18, S 12.82 (c) 13- (N-morpholyl) -3,6,9,15-tetraazabicyclo [9.3, 1] pentade-ca-1 (15), 11,13-triene 86 g (114 mmol) of the title compound Example 22b said compound is introduced into 270 ml of concentrated sulfuric acid and stirred for 48 hours at 100 ° C. Cool to 0 ° C and drop by drop of 1.35 L of absolute ether. The precipitate is aspirated and suspended in 100 ml of aqueous sodium hydroxide (pH 12). It is extracted 7 times with 150 ml of chloroform and the combined organic phases are dried over magnesium sulfate. After evaporation in vacuo, 22.26 g (67% of theory) of product is obtained in the form of a yellowish oil which crystallizes on standing.

Analysis: Calculated: C 61.82, H 8.65, N 24.04, 0. 5.49 Found: C 61.89, H 8.59, N 24.13 d) 13- (N-morpholino) - 3,6,9-tris- (carboxymethyl) -3,6,9,15-tetra-traazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 1

Dissolve g (34.3 mmol) of the title compound of Example 22c in 150 ml of water and add 12.85 g (136 mmol) of chloroacetic acid. Adjust to pH 9.5 with 6N

59 DK 171097 B1 potassium hydroxide. Stir for 12 hours at 45 ° C, maintaining the pH between 9.5 and 10 by the addition of 6N potassium hydroxide. Adjust with concentrated hydrochloric acid to pH 2 and purify on ion exchangers as described in Example 1d. Crystallized from on methanol / acetone gives 9.9 g (62% of theory) of the title compound as a strong hygroscopic solid.

Analysis: Calculated: C 54.18, H 6.71, N 15.05, 0.24.06 Found: C 54.09, H 6.82, N 15.01 e) Gadolinium complex of 13- (N-morpholino ) -3,6,9-tris- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 9 g (19) (33 mmol) of the title compound of Example 22d is dissolved in 60 ml of deionized water, and 3.5 g (9.67 mmol) of sodium oxide are added. The mixture is stirred for 3 hours at 90 ° C and the pH is maintained by the addition of acetic acid of 5.5. The solution is filtered and passed over a column filled with poly (4-vi new 1-pyridine). After treatment with activated charcoal, it is again filtered and freeze-dried.

Yield: 10.9 g (91% of theory) in the form of an amorphous powder containing, according to analysis, 9.87% water.

25

Analysis:

Calculated: C 40.70, H 4.55, N 11.30, 0 18.07, Gd 25.37 Found: C 40.63, H 4.64, N 11.25, Gd 25.28 Example 23 a) 13-chloro-3,6,9-tris- (benzyl) -3,6,9,15-tetraazabicyclo- [9,3,1] pentadeca-1 (15), 11,13-triene 1 9, 3 g (38.62 mmol) of the title compound of Example 5c and 21.36 g (154.5 mmol) of potassium carbonate are dissolved in 200 ml of di methylformamide and heated to 70 ° C. Within 60 minutes for 30 minutes, 26.43 g (154.5 mmol) of benzyl bromide are added dropwise and stirred for 24 hours at 70 ° C.

The solvent is removed under vacuum and the residue is taken up in 250 ml of 3N sodium hydroxide. Extract 5 times with 150 ml of methylene chloride and dry the organic phases over magnesium sulfate. After evaporation in vacuo, chromatograph on silica gel (eluent: isopropanol / triethylamine = 20: 1).

Yield: 17.97 g (91% of theory) in the form of a pale yellow oil.

Analysis: Calculated: C 75.20, H 6.90, N 10.97, Cl 6.93

Found: C 75.11, H 6.98, N 10.85, Cl 7.06 b) 13-Carboxy-3,6,9-tris- (benzyl) -3,6,9,15-tetraazabicyclo [not] [9,3,1] pentadeca-l (15), 11,13-triene

To 1.95 g (79.44 mmol) of magnesium chips is added dropwise a 2 ° solution of 17.5 g (34.24 mmol) of the title compound of Example 23a in 80 ml of 1,2-dimethoxyethane and heated to boiling. A solution of 6.43 g (34.24 mmol) of 1,2-dibromoethane in 40 ml of 1,2-dimethoxyethane is added over a period of 12 hours. The cubes are cooled on an ice-25 bath and the solution is gently shaken on 10 g of dry ice. After stirring at room temperature for 3 hours, add 200 ml of water and adjust to pH 4 with hydrochloric acid. Evaporate to dryness and boil the residue with 200 ml of ethanol. After removing the magnesium salts, evaporate again to dryness, 3 ° and the residue is chromatographed on silica gel (eluent: chloroform / methanol / triethylamine = 20/15/1).

Yield: 5.16 g (29% of theory) as a yellowish solid.

Analysis: Calculated: C 76.27, H 6.79, N 10.10, = 6.16

Found: C 76.19, H 6.88, N 10.71 61 c) 13- (Morpholinocarbony) -3,6,9-tris- (benzyl) -3,6,9,15-tetrahydrocarbonyl; azabicyclo [9.3, 1] pentadeca-1 (15), 11,13-triene 5.0 g (9.62 mmol) of the title compound of Example 23b, 922 mg (10.58 mmol) ) morpholine and 1.43 g (10.58 mmol) of 1-hydroxy-1H-benzotriazole hydrate are dissolved in 10 ml of absolute dimethylformamide and cooled to 0 ° C. 2.18 g (10.58 mmol) of dicyclohexy1 carbod are added in imide and stirred for 1 hour at 0 ° C and then overnight at room temperature. The solution 10 is poured onto 180 ml of ice water and extracted 3 times with 150 ml of chloroform. After drying the organic phase over magnesium sulfate, evaporate in vacuo. The residue is chromatographed on silica gel (eluent: chloroform / methanol / triethylamine = 20/5/1).

15

4.22 g (88% of theory) of the title compound are obtained in the form of a colorless oil.

Analysis: Calculated: C 75.48, H 7.19, N 11.90, 0. 5.44 Found: C 75.37, H 7.27, N 11.83 d) 13- (morpholinocarbonyl) -3, 6,9,15-tetraazabicyclo [9,3,1] pen-tadeca-1 (15), 11,13-triene 4.1 g (6.96 mmol) of the compound mentioned in Example 23c is dissolved in 250 ml of ethanol and 0.5 g of Pear 1man catalyst (20% palladium hydroxide on charcoal) is added. After hydrogenation for 24 hours in autoclave (50 ° C and 3 bar hydrogen rich), the catalyst is aspirated and evaporated under vacuum. The residue is recrystallized from 30 ml of tetrahydrofuran.

Yield: 1.85 g (83% of theory) of the title compound as a white crystalline powder.

Analysis: Calculated: C 60.16, H 7.89, N 21.93, 0 10.02 Found: C 60.08, H 7.97, N 21.81 62 e) 13- (morpholinocarbonyl) ) -3,6,9-tris- (carboxymethyl) -3,6,9,15-tetraazabicyclo [9,3,1] pentadeca-1 (15), 11,13-triene 1,6 g (5, Dissolve about 0 mmol) of the title compound of Example 23d in 25 ml of water and add 1.89 g (20 mmol) of chloroacetic acid. The pH is adjusted to 9.5 with 6N potassium hydroxide. Stir for 12 hours at 45 ° C, maintaining the pH between 9.5 and 10 by the addition of 6N potassium hydroxide.

After working up on ion exchangers as described in Example 1d, after crystallization from methano / acetone, 1.66 g (67% of theory) is obtained in the form of a strong hygroscopic solid.

I5 Analysis: Calculated: C 53.54, H 6.33, N 14.19, 0 25.94 Found: C 53.41, H 6.47, N 14.08 f) Gado1 inium complex of 13 - (morpho1 inocarbony1 ) -3,6,9-1ris (carboxymethyl) -3,6,9,15-tetraazabicyclo [9.3, 1] pentadecal (15), 11,13-triene 1.5 g (30, 4 mmol) of the title compound of Example 23e is dissolved in 10 ml of deionized water log to which 551 mg (1.52 mmol) of gadolini umoxid is added. Stir for 25 hours 25 seconds 90eC. The solution is filtered and the filtrate is freeze-dried.

Yield: 1.97 g (100% of theory) in the form of a white amorphous powder, which according to analysis contains 10.1% water.

Calculated: C 40.79, H 4.36, N 10.81, 0 19.76, Gd 24.28 Found: C 40.71, H 4.44, N 10.89, Gd 24.17

Example in NMR diagnostics in vivo DK 171097 B1 nium complex of 3,6,9-1ri s- (carboxymethyl) -3,6,9,15-tetraaza-bicyclo [9,3,1] pentadeca-1 (15), 11,13-triene (Example le) pr. kg i.v. in a caudal vein. The substance was dissolved in double distilled water (pH 7.2). Recordings were made in Spin-Echo Sequence 5 Tr = 400 msec, Tg = 30 msec.

The recordings were taken before as well as 1, 23 and 43 minutes after administration of the contrast agent in the liver and tumor area.

It could be shown that the signal intensity at the tumor increased and did not decrease again within the observation period.

The results are shown in the following diagram.

30

The image shows a nude mouse Balb / c now / now with HT 29 Colon carcinoma in transverse section before and after i.v. contrast agent administration. The recordings were made in Spin-Echo-Sequenz IL =

K

400 msec, = 30 msec.

In the upper left, the mouse appears before contrast agent administration. The footage shows the liver and subcutaneous tumor. The additional recordings were taken 1, 23 and 43 minutes after administration.

35

Claims (10)

64 DK 171097 B1 1. Metal complexes of di- and tri (carboxymethyl) tri- and tetra (azabicycloalkane) derivatives of the general formula I 2-N N-Z 'X J Z 5 where. . . . is a single or double bond, A and B, which are the same or different, each is a straight or branched alkylene group having 2 to 6 carbon atoms, D is one of the groups R 3 R 3 II -CH- or = C-, E is a nitrogen atom or an oxygen atom, F is (-CH2-) n or (= CH-) n, 15. is a hydrogen atom or the group -CH2COOY, where Y is a hydrogen atom and / or a metal ion equivalent of an element having atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83, R3 is a hydrogen atom, a halogen atom or a group OR5 wherein R5 is a C1 -Cg alkyl group optionally substituted with 1-3 hydroxy groups and n is 0 or 1, as well as their salts with inorganic and / or organic bases, amino acids or amino acid amides, provided that at least two of subs the tents Z represent the group -CH2COOY, and the general formula I does not represent 3,6,9,12,18-penta-a z ab in cyclo [12.3.1] octadeca-1 (18), 14 , 16-triene-N-tetraacetic acid or 3,6,9,15-tetraazabicyclo [9.3.1] pentadeca-1 (15), 11,13-triene-N-triacetic acid or their Cu, Pb, Co -5 and Sr complexes. Compounds according to claim 1, characterized in that Y is hydrogen atoms. Compounds according to claim 1, characterized in that at least two of the substituents Y are metal ion equivalents of at least one element having atomic numbers 21-29, 42, 44 or 57-83 or at least one radioactive nucleus of an element having atomic number 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77. Pharmaceutical agents, characterized in that they contain at least one physiologically acceptable compound selected from metal complexes of di- and tri (carboxymethyl) tri and tetra (azabicycloalkane) derivatives of the general formula I according to claims 1 and 3, 6,9,12,18-pentaazabicyclo [12.3.1] octadeca-1 (18), 14,16-triene-N-tetraacetic acid and 3,6,9,15-tetra-2-azabicyclo [9.3.1] pentadeca -1 (15), 11,13 - triene-N-triacetic acid and their Cu, Pb, Co and Sr complexes, optionally together with conventional additives known from the galenic pharmacy. Use of at least one physiologically acceptable compound selected from metal complexes of di- and tri (carboxymethyl) tri- and tetra (azabicycloalkane) derivatives of the general formula I according to claim 1 and 3,6,9,12 , 18-pentaazabicyclo- [12.3.1] octadeca-1 (18), 14,16-triene-N-tetraacetic acid and 3,6,9,15-tetraazabicyclo [9.3.1] pentadeca-1 (15), 11, 13-triene-N-triacetic acid and their Cu, Pb, Co and Sr complexes for the preparation of agents for NMR, X-ray or radio diagnosis or for radio or radiotherapy. 66 DK 171097 B1 A process for the preparation of compounds of the general formula I according to claim 1 and salts thereof with inorganic and / or organic bases, amino acids or amino acid amides on the condition that at least two of the substituents Z 5 represent the group -CH 2 COOY and that the general formula I does not represent 3,6,9,12,18-pentaazabicyclo [12.3.1] octadeca-1 (18), 14,16-triene-N-tetraacetic acid or 3,6,9,15-tetrazabicyclo [ 9.3.1] pentadeca-1 (15), 11,13-triene-N-triacetic acid or their Cu, Pb, Co and Sr complexes, characterized by alkylating compounds known per se with the general formula '1-x-I HN NH J (Γ), Nn-b) /' N "where X stands for j; f or a 5- or 6-membered convertible ring to the desired ring, and wherein A and B have the meanings given in claim 1, with a halogen compound of the formula HalCH2COOY '(III) wherein Hal represents chlorine, bromine or iodine and Y' is a hydrogen atom or an acid protecting group and then, optionally after conversion of X to the 5- or 6-membered ring desired in the final product and 20, after decomposition of the protecting group Y ', if desired, the complexes of the general formula I thus obtained, wherein Y has the meaning of hydrogen, react in a manner known per se with at least one metal oxide or metal salt of an atomic number with atomic number 21-29, 31, 32, 37-39, 42-44, 49 or 57-83, and, if desired, substituting acidic hydrogen atoms still present with cations of inorganic and / or organic bases, amino acids or 5 amino acid amides.