NO179104B - Macrocyclic compound for use as NMR X-ray or radiodiagnostic agent - 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

The present invention relates to a macrocyclic compound for use as an NMR X-ray or radiodiagnostic agent.

Metal complexes came into consideration already in the early 1950s as a contrast medium in radiation diagnostics. However, the compounds then used were so toxic that they could not be used on humans. It was therefore surprising that certain complex salts are tolerated well enough by the organism that they could be used routinely in humans for diagnostic purposes. In European patent application, publication number 71564, the described dimeglumine salt of Gd-DTPA (gadolinium-III complex of di-ethylenetriaminepentaacetic acid), as the first representative of the above class of compounds, has been shown to be well suited as a contrast agent for nuclear spin tomography after clinical experience with over 7000 patients. The compounds are mostly used in connection with diseases of the central nervous system.

An important reason for the good tolerability of Gd-DTPA for clinical use is the high degree of effectiveness in nuclear spin tomography, especially in connection with several types of brain tumors. Due to the high efficiency, Gd-DTPA can be dosed in amounts of 0.1 mmol/kg body weight, which is a much lower dose than e.g. for X-ray contrast agents in many X-ray examinations.

As other representatives of complex salts, meglumine salts of Gd-DOTA (gadolinium-III complex of 1,4, 7,10-tetraazacyclo-dodecane-tetraacetic acid) for diagnostic purposes are described in German patent application no. 34 01 052.

However, there is a desire to use complexes or chelates in higher dosages. This applies in particular to the detection of certain diseases outside the central nervous system by means of nuclear spin tomography (NMR diagnostics) and quite particularly to the use of chelates as X-ray contrast agents.

In order to keep the volume load in the body as low as possible, it is necessary to use highly concentrated chelatopp solutions. The chelates known to date are not very suitable, above all because of too high an osmolality.

There is therefore a need for complexes or chelates which have a lower osmolality than the previously known chelates. At the same time, however, the compounds must fulfill the requirements for use in humans with regard to the distance between effective and toxic dose in animal experiments (therapeutic width), organ specificity, stability, contrast-enhancing effect, tolerability in the organism and solubility.

The invention has now set itself the task of providing such compounds and preparations.

Complex compounds according to the invention and solutions prepared from them meet the aforementioned requirements in a surprising manner. They have a reduced osmolality as well as a more favorable therapeutic range and/or stability and storage capacity of the solution's chemical constituents and/or organ specificity and/or contrast-enhancing effect (e.g. relaxivity) and/or tolerability in the organism (e.g. e.g. lower cardiovascular or allergic side effects) than the previously used diagnostic agents.

The use of the relevant compounds makes it possible to improve the diagnosis of numerous diseases and also without special precautions. The complexes are for the most part excreted by the organism unchanged and quickly, so that even with the use of relatively toxic metal ions and high dosages no harmful side effects are found.

The practical use of the new complexes and complex formers is also simplified due to favorable chemical stability.

Another and significant advantage of the described complexes and complex formers is their extraordinary chemical versatility. In addition to the choice of central atom, the properties can be adapted by choosing different substituents in the 5- or 6-ring in the macroring and/or of the salt former in terms of requirements for effect, pharmacokinetic effect, tolerability, solubility, handling ability, etc. one e.g. within diagnosis achieve a highly desired specificity of the compounds for particular structures in the organism, for certain biochemical substances, metabolic processes, conditions in tissues or body fluids.

Macrocyclic compounds according to the invention are characterized by the general formula I

where

- - - - denotes a single or double bond,

q denotes a number that is 0 or 1,

A and B, which may be the same or different, each represents a straight-chain or branched alkylene group of 2-6

C atoms,

D denotes a nitrogen or oxygen atom, the group =C=0, =NR<2> with R<2> in the sense of a hydrogen atom or a Ci-Cg alkyl group,

the group

or with R<3> in the sense of a hydrogen or halogen atom, a phenyl, a C1-C6 alkyl group which is optionally substituted with one or more phenyl and/or hydroxy groups, the residue OR<5>, where R<5> denotes a C1-C6 alkyl radical which is optionally substituted with 1-3 hydroxy groups; the substituent

where 1 denotes the number 0 or 1,

and R<6> and R7 independently of each other denote hydrogen atoms, the residue R<5> or phenyl or benzyl residues optionally substituted with 1-3 hydroxy groups, or R<6> and R<7> together with the nitrogen atom denote a saturated or unsaturated 5- or 6-ring which optionally contains an additional nitrogen atom, oxygen atom, sulfur atom or a carbonyl group and is optionally substituted with 1-3 residues R<5>, or one of the substituents R6 or

R<7> stands for the radical -C-R<5>, or denotes the substituent G, where G denotes a second macroring of general formula II

which is bound via a direct bond, a bis(carbonylamino) group (-NH-CO-CO-NH-) or via a C1-C20 alkylene group which optionally carries a carbonyl-(>C0)-, a carbonylamino(- NH-CO-) group or oxygen atoms and which optionally contains one or more oxygen atoms, Z-, acyl- or hydroxyacyl-substituted imino groups or one or two C-C double and/or C-C triple bonds,

where

D<1> has the same meaning as D with the exception that D<1> does not contain the substituent G or denote the residue

and F<1> has the same meaning as F with the exception that F<1> does not contain the substituent G, or denotes the residue E denotes a nitrogen, sulfur or oxygen atom, the groups

or >NR4 where R4 means-

ning of a hydroxy group, R<2> or an optionally

hydroxylated or carboxylated C 1 -C 8 alkyl group,

F denotes -(CHR<8->)n or (=CR<8->)n where n denotes 0

or 1, and R<8> has the meaning R<1> or G,

R<1> denotes a hydrogen or halogen atom or a Cx-C6 alkyl group,

Z denotes a hydrogen atom or the group -CH2COOY where Y denotes a hydrogen atom and/or a metal ion equivalent of an element with 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 denote the residue -CH2COOY, while at least two of the substituents Y denote metal ion equivalents of at least one element with atomic numbers 21-29, 42, 44 or 57-83 or at least one radionuclide of an element with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77, and the macrocyclic compound of general formula I does not contain more than one residue G, and with the proviso that the compound is not Cu-, Pb -, the Co or Sr complex of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-N-triacetic acid,

as well as its salts with inorganic and/or organic bases, amino acids or amino acid amides.

When n denotes the number 0 and the formed 5-ring is unsaturated, the double bonds are located between positions 2,3 and 4,5 in the 5-ring.

Compounds of general formula I are given the term complex former when Y has the meaning of hydrogen, and the term metal complex when at least two of the substituents Y has the meaning of a metal ion equivalent.

Elements with previously mentioned atomic numbers, which form the central ion in the physiologically tolerable complex salts, can of course also be radioactive for use as diagnostic preparations.

When the preparation is to be used for NMR diagnostics, the central ion of the complex salt must be paramagnetic. This is particularly true for 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 ytterbium(III) ions. Due to a very high magnetic moment, gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III) and iron(III) ions are particularly preferred.

When the preparation according to the invention is to be used for radiodiagnosis, the central ion must be radioactive. Radioactive isotopes of e.g. copper, cobalt, gallium, germanium, yttrium, strontium, technetium, indium, ytterbium, gadolinium, samarium and iridium will be suitable.

When the preparations are to be used for X-ray diagnostics, the central ion must be derived from an element with higher atomic numbers to provide sufficient absorption of the X-rays. Suitable diagnostic preparations contain physiologically acceptable complex salts with central ions of elements with atomic numbers 21-29, 42, 44, 57-83, e.g. the lanthanum(III) ion and previously mentioned ions in the lanthanide series.

Alkyl substituents R<1>, R2, R<3> and R4 can be straight-chain or branched hydrocarbons with up to 6, preferably up to 4 C atoms, which in the case of R3 can optionally be substituted with one or more, preferably 1- 3 phenyl and/or hydroxy groups, and in the case of R4 possibly substituted by one or more, preferably 1-3 hydroxy or carboxyl groups, and in the case of R5 optionally substituted by one or more, preferably 1-

3 hydroxy groups.

Examples of optionally substituted alkyl groups are methyl-, hydroxymethyl-, ethyl-, 2-hydroxyethyl-, 2-hydroxy-1-(hydroxymethyl)-ethyl-, 1-(hydroxymethyl)-ethyl-, propyl-, isopropyl-, 2- and 3-hydroxypropyl-, 2,3-dihydroxypropyl-, n-, sec.- and tert.-butyl-, 2-, 3- and 4-hydroxybutyl-, 2- and 3-hydroxyisobutyl-, pentyl-, 2-, 3- and 4-hydroxy-2-methyl-butyl-, 2,3,4-trihydroxybutyl-, 1,2,4-trihydroxybutyl-, cyclopentyl-, cyclohexyl-, 2,3,4,5,6 -pentahydroxyhexyl, benzyl, carboxymethyl and carboxyethyl groups.

Examples of halogen atoms in R<1> and R3 are fluorine, chlorine, bromine and iodine.

The heterocyclic 5- or 6-ring, which is formed by R<6> or R<7> during coupling of the nitrogen atom, can be saturated, unsaturated and/or substituted and possibly contain a nitrogen, oxygen, sulfur atom or a carbonyl group.

Suitable heterocyclic groups are, for example: pyrrolidinyl-, piperidyl-, pyrazolidinyl-, pyrrolinyl-, pyrazolinyl-, piperazinyl-, morpholinyl-, imidazolidinyl-, oxazolidinyl-,

thiazolidinyl, pyrroiidonyl rings.

Examples of alkylene groups A and B are particularly straight-chain and branched chains with 2-6 C atoms, preferably ethylene, methylethylene and propylene groups.

The alkylene chain to which the second macroring II is attached carries at the ends optionally a carbonyl-(CO)-, carbonyl-amino-(NH-CO)-group or oxygen atoms and contains 1-20 C atoms. The chain may be interrupted by one or more oxygen atoms, Z-, acyl- or hydroxyacyl-substituted imino groups or 1-2 C-C double and/or C-C triple bonds. However, the two macrorings can also be connected through a direct bond. Optionally hydroxylated acyl groups are in this connection acyl residues with up to 10 C atoms. For example, this applies to the acetyl, propionyl, butyryl, benzoyl and hydroxyacetyl residues.

The alkylene chain can be straight-chain or branched, saturated or unsaturated and possibly interrupted as above. It can contain up to 4 oxygen atoms and/or up to

3 carboxymethylimino groups.

Examples of alkylene chains are:

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

Macrocyclic complexes of general formula I according to the invention are prepared by alkylating compounds of general formula I' in an otherwise known manner

where l_.fi. - CT r— 11 a oeuigns the group t ener siar ror an o- ener 6-ring which can be converted into the desired ring, with a halogen compound III

where Hal denotes chlorine, bromine or iodine, and

Y' denotes a hydrogen atom or an acid protecting group, and then, optionally after conversion of X to the desired 5- or 6-ring of the final product and optionally after cleavage of the protecting groups Y', if desired reacts the thus produced complex formers with general formula I, where Y has meaning hydrogen, in otherwise known manner 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, and then, if desired, substitute any acidic hydrogen atoms with cations of inorganic and/or organic bases, amino acids or amino acid amides.

Acid protecting groups Y' can be lower alkyl, aryl and aralkyl groups, e.g. methyl, ethyl, propyl, n-butyl, t-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis(p-nitrophenyl)methyl or trialkylsilyl groups. The removal of the protective groups Y', which can be carried out before or after conversion of X to the final product's desired 5- or 6-ring, is carried out in ways known to a person skilled in the art, e.g. by hydrolysis, hydrogenolysis, alkaline saponification of the ester with alkali in aqueous-alcoholic solution at temperatures of 0-50 °C or, in the case of t-butyl esters, e.g. with trifluoroacetic acid.

Alkylation of the educt I' with the halogen compounds of general formula III is carried out in polar, aprotic solvents, such as e.g. dimethylformamide, acetonitrile, dimethylsulfoxide, aqueous tetrahydrofuran or hexamethylphosphoric acid triamide, in the presence of an acid-binding reagent such as e.g. tertiary amine (eg triethylamine, trimethylamine, N,N-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]nonen-5 [DBN], 1,5-diazabicyclo[5.4.0]undecene-5 (DBU), alkali- , alkaline earth carbonate, hydrogen carbonate or hydroxide (e.g. sodium, magnesium, calcium, barium, potassium carbonate, hydroxide or hydrogen carbonate) at temperatures between -rlO "C and 120 °C, preferably between 0 °C and 50 °C.

Transfer of an intermediate product for the desired 5- or 6-ring in the final product takes place in a manner known to the person skilled in the art. For example, mention is made of hydrogenation of e.g. pyridine rings [Advan. Catal.. 14, 203 (1963)], pyrrole rings [M. Freifelder, Practical Catalytic Hydrogenation, 577, Wiley-Interscience, New York-London-Sidney-Toronto 1971], furan rings [US-3,194,818], pyrimidine rings [J. With. Chem. 15, 291

(1972)], deoxygenation of nitroxides [E. Klingsberg, The Chemistry of Heterocyclic Compounds, vol. 14, Part 2, Inter-science Publishers New York, p. 120 (1961)], transformation and introduction of functional groups into the 5- or 6-ring, e.g. release of phenolic hydroxy groups [J. Org. Chem. 53, 5

(1988)], introduction of halogen substituents [E. Klingsberg, The Chemistry of Heterocyclic Compounds, vol. 14, Part 2, Inter-science Publishers New York, p. 341 (1961), Houben-Weyl: Methoden der organischen Chemie, Volume V/3, 651 (1962)], replacement of heteroatoms, e.g. conversion of a furan group to a pyrrole group (US-2,478,456).

Functionalization of 4-chloropyridine derivatives (e.g. azide exchange) by the phase transfer method using 18-crown-6 or tetrabutylammonium bromide as catalyst is described in "Phase Transfer Reactions" (Fluka Compendium, Volume 2, Walter E. Keller, publisher Georg Thieme, Stuttgart, New York).

Production of amides, i.e. compounds of general formula I, where R<3> denotes -C-NR6R<7>, takes place by

II

0

reaction of activated acid derivatives (e.g. mixed anhydrides or acid chlorides) with primary or secondary amines of general formula

where R<6> and R7 have previously mentioned meaning.

Suitable amines can e.g. be: dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diiso-butylamine, di-sec.-butylamine, N-methylene-propylamine, dioctylamine, dicyclohexylamine, N-ethylcyclohexylamine, diisopropenyl -amine, benzylamine, aniline, 4-methoxyaniline, 4-dimethylamino-aniline, 3,5-dimethoxyaniline, morpholine, pyrrolidine, piperidine, N-methylpiperazine, N-ethylpiperazine, N-(2-hydroxyethyl)-piperazine, N -(hydroxymethyl)-piperazine, 2-(2-hydroxymethyl)-piperidine, 4-(2-hydroxyethyl)-piperidine, 2-hydroxymethylpiperidine, 4-hydroxymethylpiperidine, 2-hydroxymethyl-pyrrolidine, 3-hydroxy-piperidine, 4-hydroxypiperidine , 3-hydroxy-pyrrolidine, 4-piperidone, 3-pyrroline, 2,6-dimethylpiperidine, 2,6-dimethylmorpholine, pyrazoline, imidazoline, oxazolidine, thiazolidine, 2,3-dihydroxypropylamine, N-methyl-2,3 -dihydroxypropylamine, 2-hydroxy-1-(hydroxymethyl)-ethylamine, N,N-bis-(2-hydroxyethyl)-amine, N-methyl-2,3,4,5,6-pentahydroxyhexylamine, 6-amino-2 ,2-dimethyl-1,3-dioxepin-5-ol, 2-hydroxyethylamine, 2-amino-1,3-propanedio l, diethanolamine, ethanolamine.

Polyhydroxyalkylamines can advantageously be used in protected form, e.g. as O-acyl derivatives or as ketals. This applies in particular when these derivatives can be produced more easily and cheaply than the polyhydroxyalkylamines themselves. A typical example is 2-amino-1-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethanol, the acetonide of 1-amino-2,3,4-trihydroxybutane, prepared according to DE-OS- 31 50 917.

The subsequent removal of protecting groups is without problems and can e.g. is carried out by treatment with an acidic ion exchanger in aqueous-ethanolic solution.

Synthesis of compounds with more than one ring can be carried out according to methods known from the literature, e.g. by means of an addition/elimination reaction of an amine with a carbonyl compound (eg, acid chloride, mixed anhydride, activated ester, aldehyde); of two amine substituted rings with a dicarbonyl compound (eg oxalyl chloride, glutardialdehyde); of two p-nitro-substituted nitroxides with bisalcoholates [see E. Klingsberg, The Chemistry of Heterocyclic Compounds, Inter-science Publishers New York, p. 514 (1961)]; of two rings which both have a nucleophilic group with an alkylene compound connected to two escape groups, or in the case of terminally placed acetyl compounds by oxidative coupling (Cadiot, Chodkiewicz in Viehe "Acetylenes", 597-647, Marcel Dekker, New York, 1969) .

The chain connecting the rings can then be modified by later reactions (e.g. hydrogenation).

The synthesis of educts of general formula I' to be alkylated is carried out by ring closure of two reactants, one of which contains the substituent X, i.e. the desired 5- or 6-ring of the final product, or an intermediate product leading to this.

The loop closure is carried out according to methods known from the literature [e.g. Org. Synth. 58, 86 (1978); Macrocyclic Polyether Syntheses, Springer Verlag Berlin, Heidelberg, New York 1982; Coord. Chem. Fox. 3, 3 (1968); Ann. Chem. 1976 (916); J. Org. Chem. 49, 110 (1984)], one of the two reactants carries two leaving groups at the end of the chain, the other carries two nitrogen atoms which nucleophilically displace these leaving groups. As an example, the reaction of end-placed dichloro, dibromo, dimethyloxy, di-tosyloxy or di-alkoxycarbonylalkylene compounds, which contain the substituent X and optionally 1-5 nitrogen atoms, with end-placed diazaalkylene compounds which optionally have 1-5 further nitrogen atoms in the alkylene chain is mentioned. The substituent X can instead also be found in the second reactant, i.e. the reactant with the terminally placed, nucleophilic nitrogen atoms. The nitrogen atoms are possibly protected, e.g. as tosylates or trifluoroacetates, and are released before the subsequent alkylation reaction in ways known from the literature (the tosylates are released, for example, with mineral acids, alkali metals in liquid ammonia, hydrobromic acid and phenol, RedAl(<R>), lithium aluminum hydride, sodium- amalgam, see e.g. Liebigs Ann. Chem. 1977, 1344; Tetrahedron Letters 1976, 3477; trifluoroacetates are liberated e.g. with mineral acids or ammonia in methanol, see e.g. Tetrahedron Letters 1967, 289).

For the production of macrocyclic compounds which are substituted differently on the nitrogen atoms (hydrogen or the group CH2COOY), these atoms can be protected with different protective groups in the educts, e.g. with tosylate or benzyl groups. These are then possibly also split off as known from the literature (preferably by hydrogenation, e.g. EP patent application no. 232751).

If diesters are used for the cyclization reaction, the diketo compounds thus produced must be reduced in ways known to those skilled in the art, e.g. with diborane.

One can also ring-close correspondingly substituted, terminally placed bisaldehydes with the desired terminally placed bis-amines; reduction of the thus prepared Schiff bases takes place as described in the literature, e.g. by catalytic hydrogenation [Heiv. Chim. Acta 61, 1376 (1978)].

Preparation of the amine which serves as starting material for the ring closure can be carried out as is known from the literature.

When starting from an N-protected amino acid, a triamine is obtained by reaction with a partially protected diamine (e.g. according to the carbodiimide method), removal of the protecting group and diborane reduction.

Reaction of a diamine formed from amino acids [Eur. J. Med. Chem.-Chim. Ther. 21, 333 (1986)] with twice the molar amount of N-protected omega-amino acid gives a tetraamine after suitable work-up.

The desired diamines can also be prepared by a Gabriel reaction from e.g. the corresponding tosylates or halides [see e.g. Inorg. Chem. 25, 4781 (1986)].

In both cases, the number of carbon atoms between the N atom can be determined by choosing diamines or amino acids that are used as coupling partners.

The thus prepared compounds of general formula I, where Y has the meaning of hydrogen, constitute complex formers. They can be isolated and purified or transferred without isolation to metal complexes of general formula I where at least two of the substituents Y denote a metal ion equivalent.

Production of metal complexes according to the invention takes place as described in German explanatory document 34 01 052, by dissolving or suspending the metal oxide or a metal salt (e.g. nitrate, acetate, carbonate, chloride or sulfate) of an element with atomic numbers 21-29, 31, 32, 37-39, 42-44, 49, 57-83 in water and/or a lower alcohol (such as methanol, ethanol or isopropanol), and reacting with a solution or suspension of the equivalent amount of complexing acid of general formula I, where Y has the meaning hydrogen, preferably at temperatures between 40 °C and 100 °C and then, if desired, substitute any acidic hydrogen atoms in acid groups with cations of inorganic and/or organic bases, amino acids or amino acid amides.

The neutralization can be carried out with inorganic bases (e.g. hydroxides, carbonates or bicarbonates) of e.g. sodium, potassium, lithium, magnesium or calcium and/or organic bases, such as primary, secondary and tertiary amines of the type ethanolamine, morpholine, glucamine, N-methyl- and N,N-dimethylglucamine as well as basic amino acids, such as e.g. lysine, arginine or ornithine.

For the production of neutral complex compounds, one can e.g. add, to acid complex salts in aqueous solution or suspension, so much of the desired bases that the neutral point is reached. The solution formed can then be evaporated to dryness. It is often an advantage to precipitate the formed neutral salts by adding water-miscible solvents, such as e.g. lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane and others), and in this way arrive at crystallisates that are easy to isolate and clean. It has proven particularly advantageous to add the desired base to the reaction mixture already during complex formation and thereby save a synthesis step.

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

This can e.g. is carried out by reacting the complex-forming acid in an aqueous suspension or solution with the oxide or salt of the element that forms the central ion and half of the amount of organic base that goes into neutralization, isolating and possibly purifying the formed complex salt and then adding the required amount inorganic base until complete neutralization. The order of base addition can also be reversed.

When using radioisotope-containing complex compounds, the preparation can take place as described in "Radiotracers for Medical Applications", Volume 1, CRC-Press, Boca Raton, Florida.

The diagnostic preparations according to the invention are likewise prepared in an otherwise known manner by suspending or dissolving complex compounds according to the invention in an aqueous medium, optionally with the addition of common additives, after which the suspension or solution is optionally sterilized. Suitable additions are, for example, physiologically usable buffers (such as tromethamine), small additions of complex formers (e.g. diethylenetriaminepentaacetic acid) or, if necessary, electrolytes such as sodium chloride or, if necessary, antioxidants such as e.g. ascorbic acid.

If suspensions or solutions of compounds according to the invention in water or physiological saline are desired for enteral administration or other purposes, the active substances are mixed with one or more common excipients for medical preparations (e.g. methylcellulose, lactose, mannitol) and /or surfactants (lecithin, Tween(<R>), Myr j(R) and/or flavoring substances for flavor improvement (e.g. ether-

ic oils).

It is in principle possible to prepare diagnostic preparations according to the invention without isolating the complex salts. In all cases, particular care must be taken to carry out the chelation so that salts and salt solutions are practically free of non-complexed and toxic metal ions.

This can e.g. is ensured by means of color indicators such as xylene orange by control titration during production. As a last resort, purification of the isolated complex salt is switched on.

Diagnostic preparations according to the invention preferably contain 1 umol to 1 mol/l complex salt and are usually dosed in quantities of 0.001-5 mmol/kg. They are suitable for enteral or parenteral use. Complex compounds according to the invention are used for: 1. NMR and X-ray diagnostics in the form of complexes with ions of elements with atomic numbers 21-29, 42, 44 and 57-83; 2. radiodiagnosis in the form of complexes with radiation isotopes of elements with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 and 77.

Preparations according to the invention meet the many requirements placed on contrast agents for nuclear spin tomography. After oral or parenteral administration, they are thus very suitable for increasing the reliability of interpretation for the image formed with the help of the nuclear spin tomograph by increasing the signal strength. Furthermore, the substances have the high degree of effectiveness necessary to burden the body with as small amounts of foreign substances as possible and a good tolerance or tolerability in the organism.

The good water solubility and low osmolality of the preparations in question make it possible to prepare highly concentrated solutions and thereby keep the volume load in the circuit within acceptable limits and equalize the dilution caused by the body fluid, i.e. that NMR diagnostics must be 100-1000 times better water-soluble than for NMR spectroscopy . Furthermore, preparations according to the invention not only exhibit high stability in vitro, but also surprisingly high stability in vivo, so that the release or exchange of ions that are complex-bound and not covalently bound - and in themselves toxic - only occurs extremely slowly during the time it takes for the new contrast agents to be completely excreted by the body.

In general, preparations according to the invention are used as NMR diagnostics in amounts of 0.001-5 mmol/kg, preferably 0.005-0.5 mmol/kg. Details of the preparations' use are discussed, e.g. in H.J. Weinmann et al., Am. J. of Roentgenology 142, 619 (1984).

Particularly low dosages (below 1 mg/kg body weight) of organ-specific NMR diagnostic compounds can be used, e.g. for the detection of tumors and heart attacks.

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

Agents according to the invention are, due to the favorable radioactive properties and high stability of the complex compounds formed, also suitable as radiation diagnostics. Details regarding use and dosage can be found e.g. in "Radiotracers for Medical Applications", CRC-Press, Boca Raton, Florida.

Another imaging method with radiation isotopes is positron emission tomography, i.e. positron-emitting isotopes such as <43>Sc, 44Sc, 52Fe, 55Co and 68Ga (Heiss, W.D., Phelps, M.E., Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).

Preparations according to the invention are excellently suitable as X-ray contrast agents, as one would particularly like to mention that there are no signs of anaphylaxis-like reactions during biochemical-pharmacological examinations of the type known for the use of iodinated contrast agents. The preparations in question are particularly useful due to the favorable absorption properties in the area for higher tube voltages in digital subtraction techniques.

The amounts of preparations according to the invention used for use as an X-ray contrast agent are in analogy with e.g. meglumine diatrizoate of 0.1-5 mmol/kg, preferably 0.25-

1 mmol/kg.

Details regarding use as an X-ray contrast agent can be found, e.g. in Barke, Rontgenkontrastmittel, G. Thieme, Leipzig (1970), and P. Thurn, E. Biicheler - "Einfuhrung in die Rontgendiagnostik" (introduction to X-ray diagnostics), G. Thieme, Stuttgart, New York (1977).

It has thus succeeded in synthesizing new complex formers, metal complexes and metal complex salts which offer new possibilities in diagnostic medicine. Above all, this is beneficial in connection with the development of new methods for image diagnosis.

The following examples shall serve to illustrate the object of the invention.

Example 1

a) 3,6,9-tris-(p-tolylsulfonyl)-3,6,9. 15- tetraazabichlor9. 3. llpentadeca- K15), 11, 13- triene

A solution of 35.2 g (200 mol) of 2,6-bis-(chloromethyl)-pyridine (dissolved in 700 ml of dimethylformamide) in the course of 3 hours. The mixture was stirred overnight at 100 °C. 2 1 of water was added to the hot solution, and the mixture was allowed to cool to 0 °C. The precipitate was filtered off and washed with water. After drying in vacuum (60 °C), it was recrystallized from acetonitrile. 92.3 g of the title compound were obtained as a colorless powder (69% of theory).

Analysis: Calculated: C 57.46, H 5.43, N 8.38, O 15.35, S 14.38

Found: C 57.39, H 5.48, N 8.35, S 14.34

b) 3, 6, 9, 15-tetraazabisvchloro9. 3. llpentadeca- K15). 11. 13-triene-tetrahydrosulfate

90.3 g (135 mmol) of the title compound from example 1a was added to 270 ml of concentrated sulfuric acid and stirred for 48 hours at 100 °C. It was cooled to 0 °C and 1.35 1 absolute ether was added dropwise. The precipitate was filtered off and stirred into 800 ml of methanol. After filtration and evaporation, it was dried in vacuum at 50 °C.

Yield: 42.6 g (52.7% of theory) of a solid which floats into air.

Analysis: Calculated: C 22.07, H 4.38, N 9.36, O 42.76, S 21.43

Found: C 22.10, H 4.42, N 9.31, S 21.40

c) 3, 6, 9 . 15- tetraazabisvchlor9. 3. llpentadeca- K15), 11, 13-triene

40.0 g (66.8 mmol) of the title compound from example 1c was dissolved in 100 ml of water and adjusted to pH 11 with 32% caustic soda. It was extracted eight times with 150 ml of methylene chloride and dried over magnesium sulfate. After evaporation in vacuo, 9.79 g (71% of theory) of a yellowish powder was obtained.

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-f9. 3. llpentadeca- K15). 11. 13- the trien

33.1 g (55.1 mmol) of the title compound from example 1c was dissolved in 170 ml of water and adjusted to pH 8.5 with 6 N potassium hydroxide. To this solution was added 20.84 g (220.5 mmol) of chloroacetic acid, adjusted to pH 9.5 with 6 N potassium hydroxide and heated to 45 °C. The mixture was stirred for 12 hours at this temperature and the pH value was kept between 9.5 and 10 by the addition of 6 N potassium hydroxide. After cooling to room temperature, it was adjusted to pH 2 with concentrated hydrochloric acid and evaporated to dryness. The evaporation residue was extracted with 300 ml ethanol/50 ml acetone, the solid was filtered off and the filtrate evaporated in vacuo. The evaporation residue was dissolved in a little water and loaded onto a cation exchange column (IR-120). After rinsing with water, the ligand was eluted with 0.5 N aqueous ammonia solution. The fractions were evaporated, taken up in a little water and put on an anion exchange column (IRA-67). First, it was washed with water, and then eluted with 0.5 N formic acid. It was evaporated in vacuo, and the evaporation residue was dissolved in slightly warm ethanol. By careful addition of acetone and cooling in an ice bath, the title compound crystallized.

Yield: 12.37 g (59% of theory) of a highly 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- tetraazabischloro9. 3♦ 11pentadeca- 1( 15). 11, 13 trien

5.0 g (13.14 mmol) of the title compound from example 1d was dissolved in 20 ml of deionized water and 2.38 g (6.57 mmol) of gadolinium oxide was added. The mixture was stirred for 3 hours at 90 °C. The solution was filtered and the filtrate freeze-dried.

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

The following relaxivity was found measured in plasma [measurements of relaxation times T1 were made in a "Minispec p20" (Bruker) at 0.46 tesla (= 20 MHz) at 40 °C]: T1 relaxivity: 7.64 (1/mmol sec.).

In comparison, dimeglumine-

the salt of the gadolinium complex

of diethylenetriaminepentaacetic-

acid (Gd-DTPA): T1 relaxivity: 4.95 (1/mmol sec). Osmolality for a 0.5 molar

dissolution at 37 °C: 0.55 (Osml/kg water).

In comparison, dimeglumine-

the salt of Gd-DTPA: 1.1 (Osml/kg water).

f ) Diprosium complex of 3, 6, 9-tris-(carboxymethyl)-3. 6. 9. 15- tetraazabicyclo9. 3. 11 pentadeca- 1( 15). 11. The 13-trien

When, for example, dysprosium oxide is used instead of gadolinium oxide, the title compound is obtained in practically quantitative yield.

Analysis: Calculated: C 37.82, H 3.92, N 10.38, 0 17.78,

Dy 30.02 Found: C 37.87, H 3.98, N 10.24, Dy 30.02

g) Ytterbium complex of 3, 6, 9-tris-(carboxymethyl)-3. 6, 9, 15- tetraazabicyclo9. 3. 11pentadeca-1(15), 11, 13-triene

When, for example, uterium oxide is used instead of gadolinium oxide, the title compound is obtained in practically quantitative yield.

Analysis: Calculated: C 37.09, H 3.85, N 10.18, 0 17.44,

Job 31:44

Found: C 37.13, H 3.94, N 10.09, Yb 31.37

h) Meqlumin salt of manganese(II)- complex of 3, 6, 9- tris-(carboxymethyl)- 3, 6, 9, 15- tetraazabicyclo-T9. 3. 11pentadeca-1( 15). 11, 13- the trien

3.0 g (7.89 mmol) of the title compound from example 1d was dissolved in 20 ml of deionized water and 907 mg (7.89 mmol) of manganese (II) carbonate was added. They stirred for 2 hours

^80 °C. The solution was filtered and the filtrate adjusted to pH 7.2 with 1 molar N-methylglucamine solution. It was then freeze-dried.

Yield: 5.56 g (100% of theory) of a pale pink, lustrous, amorphous powder which, according to analysis, contains 12.2% 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

Example 2

a) 3, 6, 9- tris-(carboxymethyl)- 3, 6, 9 , 15- tetraazabicyclo-T 9. 3. 11pentadecane

6.0 g (15.77 mmol) of the title compound from example 1d was dissolved in 200 ml of 5% hydrochloric acid and hydrogenated in an autoclave over a rhodium catalyst (5% Rh/C) at 30 bar and 45 °C. After 4 hours, the catalyst was filtered off and evaporated in vacuo. The evaporation residue was purified as described in example 1 on ion exchange columns. Crystallization from methanol/acetone gave 4.75 g (78% of theory) of an extremely hygroscopic compound.

Analysis: Calculated: C 52.83, H 7.83, N 14.50, 0 28.84

Found: C 52.94, H 7.89, N 14.37

b) Gadolinium complex of 3, 6, 9- tris-(carboxymethyl)-3, 6, 9, 15- tetraazabisichloro9. 3. 11pentadecane

To 4.3 g (11.13 mmol) of the title compound from example 2a in 20 ml of deionized water was added 2.02 g (5.57 mmol) of gadolinium oxide, and the mixture was stirred for 3 hours at 90 °C. The solution was filtered and the filtrate freeze-dried. 6.5 g (100% of theoretical) of white, fluffy powder was obtained which, according to 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

Example 3

a) 3. 6, 9- tris-(acetvl)- 3. 6, 9, 15- tetraazabisvchloro9. 3. llpentadeca- K 15), 11, 13- triene

15.8 g (76.6 mmol) of the title compound from Example 1c, 42.7 ml of triethylamine (306.4 mmol) and 50 mg of dimethylaminopyridine (DMAP) were dissolved in 300 ml of absolute methylene chloride. 28.9 ml (306.4 mmol) of acetic anhydride were added and stirred overnight at room temperature. The solvents were evaporated in vacuo and the evaporation residue taken up in 200 ml of 3% sodium carbonate solution. It was extracted twice with 150 ml of methylene chloride. After drying the organic phase over magnesium sulfate, it was evaporated in vacuo. The evaporation residue was recrystallized from ether/acetic acid. 23.93 g (94% of theory) of the title compound were obtained as 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- tetraazabiscyclo r 9. 3. 11 - pentadeca- l( 15), 11, 13- trien- 15- N- oxide

22.5 g (67.7 mmol) of the title compound from example 3a was dissolved in 100 ml of glacial acetic acid. 7.7 ml of 30% hydrogen peroxide solution were added and heated for 4 hours at 70°C. A further 3.9 ml of 30% hydrogen peroxide solution was added and further stirred for 1 hour at 70°C. Evaporated to a third in vacuo and carefully added saturated sodium carbonate solution until alkaline reaction. The mixture was extracted twice with 250 ml of methylene chloride and the organic phase was dried over magnesium sulphate. After evaporation in vacuo and crystallization from ether/acetic ester, 18.63 g (79% of theory) of the title compound were obtained as a crystalline powder.

Analysis: Calculated: C 58.60, H 6.94, N 16.08, O 16.07

Found: C 58.47, H 6.88, N 16.14

c) 13- nitro- 3, 6. 9- tris-(acetyl)- 3, 6, 9, 15- tetraazabisvchloro9. 3. 11pentadeca-1(15). 11, 13-triene-15-N-oxide 17 g (48.8 mmol) of the title compound from example 3b was dissolved in 40 ml of 90% sulfuric acid and heated to 60 °C. 14 ml of concentrated nitric acid (d = 1.36) were added dropwise to this solution, and the mixture was stirred for 3 hours at 60 °C. The mixture was poured onto ice, the precipitate was filtered and washed with plenty of water. After drying in vacuum, an orange powder was obtained which is recrystallized from acetone.

Yield: 9.2 g (48% of theory) of yellow rhombic crystals.

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- tetraazabisvchlor9. 3. llpentadeca- K15). 11. 13-triene-15-N-oxidl

A freshly prepared solution of ethylene glycol disodium in dimethylformamide (prepared from 620 mg of ethanediol and 600 mg of sodium hydride [80% suspension in paraffin] in 15 ml of anhydrous dimethylformamide) was added over 10 min. to a solution of 8 g (20.34 mmol) of the title compound from example 3c dropwise at 50 °C and was stirred overnight at this temperature. 10 ml of water was added and evaporated in vacuo. The evaporation residue was chromatographed on silica gel (propellant: methanol/32% aqueous ammonia solution = 10/1). After crystallization from ether/acetic ester, 3.15 g (41% of theory) of a yellowish, crystalline powder was 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-T3, 6, 9- tris-(acetyl)-3. 6, 9, 15- tetraazabicyclo9. 3. llpentadeca- K15). 11, 13-trienl

3 g (3.97 mmol) of the title compound from example 3d was dissolved in 100 ml of ethanol, 1 ml of concentrated hydrochloric acid was added and hydrogenated over Pd/C. The catalyst was filtered off, evaporated in vacuo and the evaporation residue taken up in 50 ml of 3% sodium carbonate solution. The mixture was extracted twice with 100 ml of methylene chloride. After drying the organic phase over magnesium sulfate, the solvent was evaporated in vacuo and crystallized from ether/acetic ester.

Yield: 2.87 g (87% of theory) 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) 13, 13'- ethylenedioxv- bis- f 3, 6, 9, 15- tetraazabisichloro9. 3. 11pentadeca-1(15), 11, 13-triene1

2.5 g (3.46 mmol) of the title compound from Example 3e and 4.66 g (41.5 mmol) of potassium tert-butylate were dissolved in 40 ml of dioxane under a nitrogen atmosphere and heated overnight under reflux. It was evaporated in vacuo, the evaporation residue was taken up in 50 ml of water and 2 N caustic soda was added until pH 10. After six extractions with portions of 80 ml of methylene chloride, it was dried over magnesium sulfate, and the solvent was evaporated in vacuum.

Yield: 1.55 g (95% of theory) light yellow oil which crystallizes 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-T3, 6, 9- tris-(carboxymethyl)-3, 6, 9. 15- tetraazabicyclo9. 3. llpentadeca- K15), 11, 13-trienl

1.4 g (2.97 mmol) of the title compound from example 3f was dissolved in 20 ml of water and 2.25 g (23.8 mmol) of chloroacetic acid was added. It was adjusted with 6 N potassium hydroxide at pH 9.5. The mixture was stirred for 12 hours at 45 °C and the pH value was adjusted to 9.5-10 with 6 N potassium hydroxide. The pH was adjusted to 2 with concentrated hydrochloric acid and the product was purified on ion exchange columns as indicated in example 1d. Crystallization from ethanol/acetone gave 1.3 g (57% of theory) of the title compound as a highly hygroscopic solid.

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'- ethylenedioxy- bis-f 3, 6, 9-tris-(carboxymethyl)- 3, 6, 9, 15- tetraazabisichloro9. 3. 11-pentadeca-1(15), 11, 13-trienl

1.2 g (1.47 mmol) of the title compound from example 3g was dissolved in 8 ml of deionized water and 533 mg (1.47 mmol) of gadolinium oxide was added. The mixture was stirred for 3 hours at 90 °C. The solution was filtered and the filtrate freeze-dried.

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

Analysis: Calculated: C 38.45, H 3.93, N 9.94, 0 19.87,

Gd 27.90

Found: C 38.60, H 3.93, N 10.03, Gd 27.79

Example 4

a) 13- ethynyl- 3, 6, 9- tris-(acetyl)- 3, 6, 9, 15- tetraazabisvchloro9. 3. 11pentadeca-1( 15). 11. 13-triene-15-N-oxvd 10 g (25.42 mmol) of the title compound from example 3c was dissolved in 200 ml of dimethoxyethane (DME) under a nitrogen atmosphere. 1.22 g (25.42 mmol) of sodium acetylide (18% suspension in xylene/light mineral oil) was added and stirred overnight at room temperature. 10 ml of water was added and evaporated to dryness. The evaporation residue was chromatographed on silica gel (eluent: methanol/acetone = 1:1). Crystallization from ether/acetic ester gave 5.02 g (53% of theory) of the title compound as a pale yellow powder.

Analysis: Calculated: C 61.27, H 6.49, N 15.05, O 17.19

Found: C 61.31, H 6.55, N 14.94

b) 13. 13'-( 1. 3- butadivn- 1, 4- divl)- bis-( T3, 6, 9- tris-( acetyl)- 3, 6, 9, 15- tetraazabisichloro9. 3. 1llpentadeca- 1( 15). 11. 13- trienl- 15- N- oksvd)

4.75 g (12.75 mmol) of the title compound from example 4a was dissolved in 200 ml of pyridine and 2.52 g (25.5 mmol) of copper (I) chloride was added. The solution was saturated with oxygen and stirred for 2 days at room temperature. An oxygen atmosphere had to be maintained at all times. After evaporation of the solution in vacuo, the evaporation residue was chromatographed on silica gel (eluent: methanol/acetone = 1/2). Crystallization from ether/acetic ester yields 2.7 g (57% of theory) of et

pale yellow powder.

Analysis: Calculated: C 61.27, H 6.49, N 15.05, O 17.19

Found: C 61.31, H 6.55, N 14.94

c) 13, 13'-( 1. 3- butadivn- l. 4- divl)- bis- r3. 6. 9- tris-(acetyl)- 3. 6. 9. 15- tetraazabicyclo9. 3. llpentadeca-1( 15). 11. 13- trienl

2.5 g (3.37 mmol) of the title compound from example 4b was dissolved in 50 ml of glacial acetic acid and heated to 60 °C. 1.88 g (33.65 mmol) of iron powder was added and stirred for 2 hours at 60 °C. The solid was filtered off and the filtrate evaporated to dryness. The residue was taken up in 100 ml of 3% sodium carbonate solution and extracted three times with 100 ml of chloroform. After drying over magnesium sulfate, the solvent was evaporated and the evaporation residue crystallized from ether/acetone.

Yield: 2.08 g (87% of theory) colorless powder.

Analysis: Calculated: C 64.21, H 6.52, N 15.77, O 13.51

Found: C 64.31, H 6.60, N 15.68

d) 13. 13'-( 1. 3- butadivn- l. 4- divl)- bis- T3. 6. 9. 15- tetra-azabisvklof9. 3. llpentadeca- K15). 11. 13- trienl

1.9 g (2.67 mmol) of the title compound from Example 4c was dissolved in 20 ml of dioxane under a nitrogen atmosphere. 2.4 g (21.38 mmol) of potassium tert-butylate were added and boiled overnight under reflux. The solvent was evaporated in vacuo and the evaporation residue taken up in 20 ml of water. The pH was adjusted to 10 with 2 N caustic soda and extracted six times with 60 ml of methylene chloride. After drying the organic phases over magnesium sulphate, it was evaporated in vacuo.

Yield: 1.09 g (89% of theory) 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- butadivn- 1, 4- divl)- bis- f 3. 6. 9- tris-( carboxymethyl)- 3, 6. 9. 15- tetraazabisvclo T 9. 3. 11 -

pentadeca- K15), 11, 13- trienl

1.0 g (2.18 mmol) of the title compound from example 4d was dissolved in 15 ml of water and 1.65 g (17.44 mmol) of chloroacetic acid was added. The pH was adjusted to 9.5 with 6 N potassium hydroxide and

stirred for 12 hours at 45 °C. The pH value was maintained between 9.5 and 10 with 6 N potassium hydroxide. After acidification with concentrated hydrochloric acid, it was purified on ion exchange columns as described under example ld. Crystallization from methanol/acetone gave 1.07 g (61% of theory) of a highly hygroscopic solid.

Analysis: Calculated: C 56.57, H 5.75, N 13.89, O 23.79

Found: C 56.64, H 5.81, N 13.79

f) Gadolinium complex of 13, 13'-(1,3-butadivn-1,4-divl)-bis-T3,6,9-tris-(carboxymethyl)-3,6,9,15-tetraaza-biscyclo9. 3. 11pentadeca-1( 15). 11, 13- trienl

900 mg (1.116 mmol) of the title compound from Example 4e was dissolved in 8 ml of water and 404 mg (1.116 mmol) of gadolinium oxide was added. After stirring for 3 hours at 90 °C, the solution was filtered and the filtrate freeze-dried.

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

Analysis: 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

Example 5

a) 13-chloro-3,6,9-tris-(acetyl)-3,6,9,15-tetraazabicyclo-f9. 3. 11pentadeca-1(15),11,13-triene-15-N-oxide

7.3 g (18.56 mmol) of the title compound from Example 3c was heated in 50 ml of acetyl chloride for 4 hours at 50 °C. The mixture was evaporated in vacuo and the evaporation residue dissolved in 200 ml of 3% sodium carbonate solution. This was extracted three times with 100 ml of chloroform and dried over magnesium sulfate. After evaporating the solvent in vacuo, it was recrystallized from ether/acetic acid.

Yield: 6.18 g (87% of theory) colorless crystalline powder.

Analysis: Calculated: 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- tris-(acetyl)- 3. 6. 9 , 15- tetraazabisichloro9. 3. 11pentadeca-1(15). 11. 13- the trien

6.0 g (15.67 mmol) of the title compound from example 5a was dissolved in 300 ml of ethanol. 1 ml of concentrated hydrochloric acid was added and hydrogenated over Pd/C. After completion of hydrogen absorption, the catalyst was filtered off and the mixture evaporated in vacuo. The evaporation residue was dissolved in 100 ml of 3% sodium carbonate solution and extracted twice with 100 ml of chloroform. The organic phases were dried over magnesium sulfate and evaporated in vacuo. Crystallization of the evaporation residue from ether/acetic ester gave 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, O 13.08,

Cl 9.66

Found: C 55.57, H 6.38, N 15.31, Cl 9.59

c) 13- chloro- 3, 6. 9, 15- tetraazabichloro 9. 3. 11pentadeca-1( 15), 11. 13- triene

5.1 g (13.9 mmol) of the title compound from example 5b was dissolved in 50 ml of dioxane under nitrogen. 6.24 g (55.6 mmol) of potassium tert-butylate was added and the mixture was refluxed overnight. One proceeded as under example 4d.

Yield: 3.01 g (90% of theory) pale yellow 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

d) 13-chloro-3,6,9-tris-(carboxymethyl)-3,6,9,15-tetraaza-bicyclo9. 3. 11pentadeca-1(15), 11, 13-triene

2.38 g (11.65 mmol) of the title compound from example 5c was dissolved in 30 ml of water and 4.4 g (46.6 mmol) of chloroacetic acid was added. The pH was adjusted to 9.5 with 6 N potassium hydroxide. It was stirred for 12 hours at 45 °C, and the pH value was maintained at 9.5-10 by the addition of 6 N potassium hydroxide. After work-up as described in example 1d and crystallization from methanol/acetone, 3.23 g (67% of theory) of the title compound were obtained as a solid which floats out under an air atmosphere.

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

e) Gadolinium complex of 13- chloro- 3. 6, 9- tris-(carboxymethyl)- 3, 6, 9, 15- tetraazabisvchloro9. 3. 11-pentadeca-1(15), 11, 13-triene

3.23 g (7.78 mmol) of the title compound from example 5d was dissolved in 20 ml of deionized water and 1.41 g (3.89 mmol) of gadolinium oxide was added. The mixture was stirred for 3 hours at 90 °C. The solution was filtered and the filtrate freeze-dried.

Yield: 4.9 g (100% of theory) of white, amorphous 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 27.63

Found: C 35.94, H 3.57, Cl 6.17, Gd 27.56 T1 relaxivity (1/mmol sec), 40 °C, water, 20 MHz: 5.44.

Example 6

a) 3, 6. 9. 15- tetraazabisvchlor9. 3. llpentadeca- K15), 11, 13-trien- 15- N- oxide

4.5 g (12.9 mmol) of the title compound from example 3b was dissolved in 40 ml of dioxane under nitrogen. 5.8 g (51.7 mmol) of potassium tert-butylate were added, and the mixture was boiled overnight under reflux. After working up as in example 3f, 2.61 g (91% of theoretical) of pale yellow oil was obtained which crystallized 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

b) 3,6,9-tris-(carboxymethyl)-3,6,9,15-tetraazabicyclo-f9. 3. llpentadeca- K15), 11. 13- trien- 15- N- oxvd

2.4 g (10.77 mmol) of the title compound from example 6a was dissolved in 30 ml of water and 4.1 g (43.4 mmol) of chloroacetic acid was added. It was adjusted to pH 9.5 with 6 N potassium hydroxide. The mixture was stirred for 12 hours at 45 °C and the pH value was maintained at 9.5-10 with 6 N potassium hydroxide. After working up as in example ld and crystallization from ethanol/acetone, 2.7 g (63% of theoretical) were obtained

highly hygroscopic powder.

Analysis: Calculated: C 51.51, H 6.10, N 14.14, O 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- tetraazabisvchlor9. 3. 11pentadeca-1( 15). 11. 13-triene-15-N-oxide

2.1 g (5.3 mmol) of the title compound from example 6b was dissolved in 15 ml of deionized water and 935 mg (2.65 mmol) of gadolinium oxide was added. The mixture was stirred for 3 hours at 90 °C. The solution was filtered, and the filtrate was freeze-dried.

Yield: 3.2 g (100% of theory) 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

Example 7

a) 3, 6, 9- tris-(p- tolylsulfonyl)- 3, 6. 9- triaza- 14- oxa-biscyclof 9. 2. 11tetradeca- 1( 13), 11- diene

To 121.9 g (200 mmol) of N,N',N''-tris-(p-tolylsulfon-yl)-diethylenetriamine-N,N-disodium salt in 1600 ml of dimethylformamide was added at 100 °C a solution of 33 g (200 mmol) of 2,5-bis-(chloromethyl)-furan in 700 ml of dimethylformamide over 3 hours by dropwise addition. The mixture was stirred overnight at 100 °C. 2 1 of water was added to the hot solution. It was cooled to 0 °C. The precipitate was washed with plenty of water and dried in vacuum (60 °C). After crystallization from acetonitrile, 88.14 g (67% of theory) of white powder was obtained.

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-bicyclo9. 2. 11tetradeca-1( 13), 11- diene

30 g (45.61 mmol) of the title compound from Example 7a was suspended in 500 ml of liquid ammonia at -5-40 °C. Then was added within 30 min. 10.49 g (456.1 mmol) of sodium, and the mixture was stirred for 3 hours at 4-40 °C. The excess sodium was destroyed by the careful addition of ethanol (decolorization), and the ammonia was evaporated. The residue was dissolved in 100 ml of water and adjusted to pH 11 with 6 N caustic soda. It was extracted six times with 150 ml of methylene chloride, the organic phase was dried over magnesium sulphate and evaporated in vacuo. The evaporation residue was chromatographed on silica gel (eluent: acetonitrile/water/32% ammonia solution = 10/3/1).

Yield: 3.95 g (45% of theory) 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

c) 3, 6, 9- tris-(ethoxycarbonylmethyl)- 3, 6, 9- triaza- 14-oxa- bicyclo 9. 2. 11tetradeca- 1( 13), 11- diene

To a mixture of 3.7 g (18.95 mmol) of the title compound from example 7b and 6.03 g (56.85 mmol) of anhydrous sodium carbonate in 150 ml of dimethylformamide was added dropwise at 50 °C and during 10 min. 7 ml (62.5 mmol) bromoacetic acid ethyl ester. The mixture was stirred for 4 hours at 50 °C. The solvent was evaporated off in vacuo and the evaporation residue stirred into 200 ml of methylene chloride. The solid was filtered off and the filtrate evaporated. The remaining oil was chromatographed on silica gel (eluent: methylene chloride/ethanol = 12/1).

Yield: 6.1 g (71% of theory) yellowish oil which slowly solidifies.

Analysis: Calculated: C 58.26, H 7.78, N 9.27, O 24.69

Found: C 58.17, H 7.88, N 9.19

d) Gadolinium complex of 3, 6, 9- tris-(carboxymethyl)-3, 6, 9- triaza- 14- oxa-bicyclo9. 2. 11tetradeca-1( 13). the 11th

5.0 g (11.02 mmol) of the title compound from example 7c was dissolved in 80 ml of ethanol and slowly added dropwise to 36 ml of 1 N caustic soda at 60 °C. Man heated for 30 min. during recirculation cooling. It was evaporated to dryness, the evaporation residue was dissolved in 20 ml of water and adjusted to pH 6.5 by careful addition of 2 N hydrochloric acid. After adding 2.0 g (5.57 mmol) of gadolinium oxide, it was stirred for 3 hours at 90 °C. The solution was filtered and the filtrate applied first to a short cation exchange column (IR-120) and then to a short anion-

exchanger column (IRA-67). The eluate was freeze-dried.

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

Analysis: Calculated: C 36.70, H 3.85, N 8.03, O 21.39,

Gd 30.03

Found: C 36.51, H 3.81, N 8.11, Gd 29.91

Example 8

Gadolinium complex of 3. 6, 9- tris-(carboxymethyl)- 3. 6, 9, 14-tetraazabisichloro9. 2. 11tetradeca-1(13),11-diene

10.0 g (22.04 mmol) of the title compound from example 7c was dissolved in 150 ml of ethanol and added dropwise at 60 °C to 80 ml of 1 N caustic soda. It was boiled for 1 hour under reflux and evaporated to dryness. The evaporation residue was transferred to a shaking autoclave and 3.54 g (66.12 mmol) of ammonium chloride was added. After addition of vanadium oxide catalyst (US patent 2,478,456, Chem. Abstr. 44, 665 (1950)) 100 ml of ammonia was condensed. It was heated for 12 hours at 200 °C. After evaporation of the ammonia, the residue was chromatographed on silica gel (eluent: dioxane/water/32% aqueous ammonia solution = 6/2/1). Evaporation gave approx. 5.19 g (56% of theoretical) extremely hygroscopic ammonium salt which was immediately reacted further. It was dissolved in 25 ml of deionized water, and the mixture was adjusted to pH 6.5 with 2 N hydrochloric acid. 2.24 g (6.17 mmol) of gadolinium oxide was added and stirred for 3 hours at 90 °C under nitrogen. 1 g of activated charcoal was added and the mixture was stirred for 1 hour at 90 °C. The solution was filtered and the filtrate applied first to a short cation exchange column (IR-120), then to a short anion exchange column (IRA-67). The eluate was freeze-dried.

Yield: 6.0 g (47% of theoretically calculated from the title compound from example 7c) amorphous powder which, according to analysis, contains 11.1% water.

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

Example 9

a) 15-Methoxy-3,6,9-tris-(p-tolylsulfonyl)-3,6,9-triazabichloro9. 3. llpentadeca- K15), 11, 13- triene

182.85 g (300 mmol) of N,N',N''-tris-(p-tolylsulfonyl)-diethylenetriamine-N,N''-disodium salt were dissolved in 2.4 L of dimethylformamide and heated to 100°C. A solution of 88.2 g (300 mmol) of 2,6-bis-(bromomethyl)phenolmethylether in dimethylformamide was added dropwise over the course of 3 hours. The mixture was stirred overnight at 100 °C. 3 1 of water were added to the hot solution and cooled to 0 °C. The precipitate was washed with plenty of water and dried under vacuum (60 °C). Crystallization from acetonitrile afforded 119.3 g (57% of theory) of the title compound as a light cream-colored powder. Analysis: Calculated: C 58.51, H 5.63, N 6.02, O 16.05,

S 13.78

Found: C 58.41, H 5.68, N 6.13, S 13.70

b) 15- hydroxy- 3, 6, 9- triazabicyclo9. 3. llpentadeca-1( 15) . 11. 13- the trien

21.75 g (573.2 mmol) of lithium aluminum hydride was carefully added to 100 g (143.3 mmol) of the title compound from example 9a in 2 l of dibutyl ether, and the mixture was heated overnight under reflux. The mixture was cooled in an ice bath, and excess lithium aluminum hydride was decomposed with ethanol and then with water. It was evaporated to dryness in vacuo, the evaporation residue was dissolved in 1 1 2 N sodium hydroxide solution and extracted ten times with 200 ml of chloroform. After drying over magnesium sulfate, it was evaporated in vacuo, and the residue was chromatographed on silica gel (eluent: methanol/32% aqueous ammonia solution = 10/1).

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

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

Found: C 65.18, H 8.60, N 19.10

c) 15-hydroxy-3.6.9-tris-(tert.-butoxycarbonylmethyl)-3. 6, 9- triazabicyclo9. 3. llpentadeca- K15), 11, 13- triene

8.3 g (37.50 mmol) of the title compound from example 9b was dissolved in 250 ml of dimethylformamide and 15.55 g (112.5 mmol) of anhydrous potassium carbonate was added. It was drenched in

within 30 min. 16.3 ml (112.5 mmol) bromoacetic acid tert-butyl ester and stirred overnight at room temperature. The solvent was evaporated to dryness, the evaporation residue was dissolved in 300 ml of water and extracted three times with 150 ml of methylene chloride. The organic phase was dried over magnesium sulfate and evaporated under vacuum. The remaining oil was chromatographed on silica gel (eluent: methylene chloride/methanol = 15/1).

Yield: 13.32 g (63% of theory) of the title compound as 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- triaza-bicyclof 9. 3. llpentadeca- K15), 11, 13- triene

13.0 g (23.06 mmol) of the title compound from Example 9c was dissolved in 150 ml of trifluoroacetic acid and stirred overnight at room temperature. It was evaporated in vacuo. The evaporation residue was taken up in a little water and purified as described in example ld

on ion exchange columns. Crystallization from methanol/acetone gave 6.5 g (71% of theory) of the title compound as a powder which readily floats in air.

Analysis: Calculated: C 54.67, H 6.37, N 10.63, O 28.33

Found: C 54.51, H 6.30, N 10.57

e) Gadolinium complex of 15-hydroxy-3.6,9-tris-(carboxymethyl)-3,6,9-triazabichloro9. 3. Upentadeca-1( 15), 11. 13- triene

4.0 g (10.1 mmol) of the title compound from example 9d was dissolved in 25 ml of deionized water and 1.84 g (5.05 mmol) of gadolinium oxide was added. It was stirred for 3 hours at 90 °C, 1 g of activated charcoal was added, and it was stirred for a further 1 hour at this temperature. The solution was filtered, and the filtrate was freeze-dried. 6.04 g (96% of theoretical) of amorphous powder is obtained which, according to analysis, contains 13.5% water.

Analysis: Calculated: C 39.33, H 4.04, N 7.65, O 20.38,

Gd 28,61

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

Example 10

a) 6- benzvl- 3, 9- bis-(p- tolvvsulfonyl)- 3. 6. 9 , 15- tetra-azabicyclo9. 3. 11pentadeca-1(15), 11. 13-triene

To 109.12 g (200 mmol) N,N<*>'-bis-(p-tolylsulfonyl)-N'-benzyl-diethylenetriamine-N,N''-disodium salt in 1500 ml of dimethylformamide was added at 100 "C in the course of 3 hours, a solution of 35.2 g (200 mmol) of 2,6-bis-(chloromethyl)-pyridine (dissolved in 700 ml of dimethylformamide) was added dropwise. The mixture was stirred overnight at 100 °C. 2 L of water were added dropwise to the hot solution, and it was cooled to 0 °C. The precipitate was washed several times with water and was dried in vacuo (60 °C). Crystallization from acetonitrile/ether gave 78.6 g (65% of theoretical ) cream-colored powder.

Analysis: Calculated: C 63.55, H 6.00, N 9.26, O 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 T 9 . 3. 11 pentadeca-1( 15), 11. 13- triene

To 75 g (124 mmol) of the title compound from example 10a in 1.5 1 of dibutyl ether was carefully added 9.41 g (248 mmol) of lithium aluminum hydride, and it was heated overnight under reflux. After cooling in an ice bath, the excess lithium aluminum hydride is broken down with ethanol and water. It was evaporated to dryness, taken up in 500 ml of water and adjusted to pH 11 with 6 N potassium hydroxide. It was extracted six times with 100 ml of chloroform, the organic phase was dried over magnesium sulphate and evaporated in vacuo. Chromatography on silica gel (eluent: ethanol/32% aqueous ammonia solution = 12/1) gave 22.4 g (61% of theory) of yellowish oil which solidifies to a glassy mass.

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-tetraazabicyclo f 9. 3. 11pentadeca- 1( 15), 11, 13- triene 10 g (33.74 mmol) of the title compound from example 10b was dissolved in 300 ml of dimethylformamide. 7.13 g (67.48 mmol) of anhydrous sodium carbonate were added and heated to 50 °C.

One dripped in within 15 min. 8.3 ml (74.2 mmol) bromoacetic acid ethyl ester and further stirred overnight at 50 °C. The solvent was evaporated in vacuo, the evaporation residue was stirred with 2 x 350 ml of methylene chloride, filtered and evaporated. The remaining oil was 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.

Analysis: Calculated: C 66.64, H 7.74, N 11.96, O 13.66

Found: C 66.51, H 7.81, N 11.88

d) 3, 9- bis-(carboxymethyl)- 3, 6, 9, 15- tetraazabicyclo9. 3. 11pentadeca-1( 15). 11. 13-triene 12 g (25.6 mmol) of the title compound from example 10c was dissolved in 100 ml of ethanol and heated at 60 °C. 32 ml of 2 N caustic soda was added to the solution, and the mixture was boiled for 1 hour under reflux. It was evaporated to dryness, and the evaporation residue was dissolved in 200 ml of 5% acetic acid. The solution was hydrogenated over Pd/C. After completion of hydrogen uptake, the catalyst was filtered off, evaporated in vacuum and purified as described in example 1d by ion exchange columns. Crystallization from ethanol/acetone gave 6.52 g (79% of theory) of highly hygroscopic solid.

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) Manqan( II)- complex of 3, 9- bis-(carboxymethyl)-3, 6, 9, 15- tetraazabisichloro9. 3. llpentadeca- K15). 11. The 13-triene 4 g (12.4 mmol) of the title compound from example 10d was dissolved in 20 ml of deionized water and 1.43 g (12.4 mmol) of manganese (II) carbonate was added. The mixture was heated for 2 hours at 80 °C. The solution was first applied to a short cation exchange column (IR-120), then a short anion exchange column (IRA-67). The eluate was boiled with 1 g of activated carbon for 1 hour under reflux and was filtered. The filtrate was freeze-dried. 4.4 g (87% of theory) of pale pink, lustrous, amorphous powder was obtained.

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

Example 11

a) 3,6-bis-(p-tolylsulfonyl)-3,6,12-triazabichloro6. 3. 11- dodecal (12). 8, 10- the three

To 82.48 g (0.2 mol) of N,N'-bis-(p-tolylsulfonyl)-ethylenediamine disodium salt in 1600 ml of dimethylformamide was added at 100 °C a solution of 35.2 g (0.2 mol) 2,6-bis-(chloro-methyl)-pyridine (dissolved in 700 ml of dimethylformamide) during 3 hours by dropwise addition. Stirring was continued overnight at 110 °C. To the hot solution was added 2 l of water, the precipitate was filtered off and washed with plenty of water. After drying in vacuum (60 °C), it was recrystallized from acetonitrile.

Yield: 67.9 g (72% of theory) cream-colored 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- triazabisvchlor6. 3. 11dodeca-l( 12). 8. 10-triene trihydrosulphate

67.0 g (142 mmol) of the title compound from example 11a was added to 200 ml of concentrated sulfuric acid and stirred for 48 hours at 100 °C. The mixture was cooled to 0 °C, and 1 1 absolute ether was added dropwise. The precipitate was filtered off and stirred into 600 ml of methanol. It was filtered and evaporated to dryness. Drying in vacuo (60 °C) gave 44.17 g (68% of theory) of the title compound as 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

c) 3, 6, 12- triazabicyclo6. 3. lldodeca- K12). 8. 10-triene 42.0 g (91.8 mmol) of the title compound from example

11b was dissolved in 100 ml of water and adjusted to pH 11 with 32% caustic soda. It was extracted six times with 200 ml of methylene-

chloride, and the combined phases were dried over magnesium sulfate. After evaporation in vacuo, 11.24 g (75% of theory) of pale yellow oil were 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- triazabiscyclo T 6. 3. 11 - dodeca- 1( 12). 8. 10- trien

10 g (61.27 mmol) of the title compound from example 1c was dissolved in 100 ml of water and 17.37 g were added

(183.8 mmol) of chloroacetic acid. It was adjusted to pH 9.5 with 6 N potassium hydroxide, and the mixture was heated to 45 °C. It was stirred for 12 hours at this temperature, whereby the pH value was kept at 9.5-10 by the addition of 6 N potassium hydroxide. It was cooled and purified as described in example 1d on ion exchange columns. Crystallization from ethanol/acetone gave 11.47 g (67% 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) Manqane complex of 3, 6- bis-(carboxymethyl)- 3, 6, 12- tri-azabicyclo f 6. 3. 11dodeca- 1( 12), 8, 10-triene

10.0 g (35.8 mmol) of the title compound from example lid was dissolved in 40 ml of deionized water and 4.12 g (35.8 mmol) of manganese (II) carbonate was added. The mixture was stirred for 2 hours at 80 °C. The solution was applied to a short anion and cation exchange column, and the eluate was stirred with 1 g of activated carbon for 1 hour at 80 °C. The mixture was filtered, and the filtrate was freeze-dried.

Yield: 12.7 g (96% of theory) of the title compound as an amorphous powder containing 11.3% water by 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 qadolinium complex of 3, 6, 9-tris-(carboxymethyl)- 3, 6, 9, 15- tetraazabicyclo[ 9. 3. 11- pentadeca- 1 ( 15), 11. 13- triene

534.63 g (1 mol) of the compound from example 1e was dissolved in 1200 ml of water with a degree of purity pro injectione (p.i.). After addition of 24.62 g (50 mmol) monohydrate of the calcium trisodium salt of DTPA, CaNa3DTPA, it was filled with water p.i. to 2000 ml. The solution was ultrafiltered, filled into ampoules, was heat sterilized and is ready to use for parenteral administration.

Example 13

Preparation of meglumine salt solution of the manganese(II) complex of 3,6,9-tris-(carboxymethyl)-3,6,9,15-tetraazabichloro9. 3. llpentadeca- K15), 11, 13- triene

34.92 g (50 mmol) of compound from example 1h (water content 12.29%) was dissolved in 65 ml of water (p.i.). After addition of 492 mg (1 mmol) monohydrate of the calcium trisodium salt of DTPA, CaNa 3 DTPA, it was filled with water p.i. to 100 ml. The solution was then ultrafiltered, filled into ampoules and heat sterilized, after which it is ready for parenteral application.

Example 14

Composition of a powder for the preparation of a suspension for oral administration

4,000 g gadolinium complex according to example and 3,895 g mannitol

0.100 g polyoxyethylene polyoxypropylene polymer 0.005 g flavoring substances

8,000 g

Example 15

Preparation of a solution of indium-111- complex of 3, 6, 9-tris-(carboxymethyl)-3, 6, 9, 15- tetraazabicyclo 9. 3. 11pentadecane

A solution of 100 µg of the compound described under example 2a in 5 ml of a mixture of 150 mmol of common salt and 150 mmol of sodium acetate solution (pH 5.8) was added to a solution of 5 ml of indium-111 chloride in 1 ml of n-hydrochloric acid. By adding 0.1 N caustic soda, the pH is adjusted to 7.2, the sterile filtered solution was filled into multi-ampoules and was freeze-dried. The residue was taken up in physiological saline solution and then constitutes a preparation suitable for radiation diagnosis.

In an analogous way, a preparation suitable for radiation therapy was obtained with yttrium-90-chloride.

Example 16

a) 3, 6, 9- tris-(p- tolylsulfonyl)- 14- oxa- 3, 6, 9- triaza-bicyclo T 9. 2. 11tetradecene

To a solution of 28.19 g (64 mmol) of 2,5-bis-(p-tosyloxymethyl)-tetrahydrofuran in 500 ml of dimethylformamide was added dropwise over the course of 2 hours at 100 °C 39.01 g (64 mmol) of N, N,'N''-tris-(p-tolylsulfonyl)-diethylenetriamine-N,N''-disodium salt in 210 ml of dimethylformamide, and it was stirred for 5 hours at 120°C. 700 ml of water was added dropwise to the hot solution, and the mixture was cooled to 0 °C. The precipitate was filtered off, washed with water and dried in vacuum at 50 °C. After recrystallization from acetone, 33.5 g of the title compound were obtained as a white powder, m.p. 175-178 °C. Analysis: Calculated: C 56.26, H 5.94, N 6.35, S 14.53,

Found: C 56.01, H 5.99, N 6.28, S 14.29

b) 14- oxa- 3, 6, 9- triazabicyclo9. 2. 11 tetradecane

30 g (45.3 mmol) of the title compound from example

16a was introduced into 90 ml of concentrated sulfuric acid and was stirred for 24 hours at 90 °C. It was cooled to 0°C and 350 ml of dry ether was added dropwise. The formed precipitate was filtered off and was dissolved in 50 ml of 40% caustic soda, after which the solution was extracted ten times with portions of 50 ml of dichloromethane. The organic phase was dried over magnesium sulfate and evaporated in vacuo. 6.23 g (69% of theory) of the title compound was obtained as a white powder.

Analysis: Calculated: C 60.27, H 10.62, N 21.08

Found: C 60.03, H 10.75, N 20.95

c) 3,6,9-tris-(carboxymethyl)-14-oxa-3,6,9-triazabicyclo r 9.2.11tetradecene 6 g (30.1 mmol) of the title compound from example 16b was dissolved in 35 ml of water, 11.38 g (120.4 mmol) of chloroacetic acid were added, and the solution was adjusted to pH 9.5 with 6 N potassium hydroxide. It was heated for 12 hours at 45 °C and during this period the pH value of 9.5-10 was maintained by adding more potash. It was then cooled to room temperature, concentrated hydrochloric acid was slowly added to pH 2, and it was evaporated in vacuo. The evaporation residue was dissolved in 100 ml of water, and the solution was applied to a cation exchange column (IR-120). The column was first washed with plenty of water, then the desired substance was eluted with 0.5 N ammonia solution, the solution was evaporated, the evaporation residue was dissolved in 100 ml of water, and this solution was put on an anion exchange column (IRA-67). It was then washed with water and eluted with 0.5 N formic acid. The acidic fractions were evaporated, and the residue was dissolved in methanol. After addition of acetone, the title compound crystallized (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- triazabicyclo9. 2. 11 tetradecane

3.73 g (10 mmol) of the title compound from Example 16c was dissolved in 15 ml of water and was stirred for 3 hours with 1.81 g (5 mmol) of gadolinium oxide at 80 °C. The resulting solution was filtered and stirred first with 0.5 g of cation exchanger (IR-120) and then with 0.5 g of anion exchanger (IRA-67), the solution was filtered again and freeze-dried. 5.07 g (91% of theory) of the title compound were obtained as a white, amorphous powder with a water content of 5.4%.

Analysis: Calculated: C 36.42, H 4.59, N 7.96, Gd 29.80

Found: C 36.30, H 4.61, N 7.82, Gd 29.59

(counted as dry matter).

a) 3.6,9-tris-(p-tolvolsulfonyl)-14-thia-3,6,9-triazabischloro9. 2. 11tetradecal (13). the 11th

60.97 g (100 mmol) of N,N,'N''-tris-(p-tolylsulfonyl)-diethylenetriamine-N,N''-disodium salt were dissolved in 800 ml of dimethylformamide and added dropwise at 50 °C and during 90 min 19.9 g (110 mmol) of 2,5-bis-chloromethylthiophene dissolved in 330 ml of dimethylformamide Stirring was continued for 90 min at 50 °C, 1 L of water was added dropwise and the precipitate formed was filtered off, washed with water and dried the residue at 50°C in a vacuum oven, and it was recrystallized from dioxane to give 47.1 g (70% of theory) of the title compound as a pale 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

b) 14- tia- 3. 6. 9- triazabisvklo f9. 2. 11tetradeca-1(13),11-diene 45 g (66.8 mmol) of the title compound from example 17a was dissolved in 130 ml of concentrated sulfuric acid and was stirred for 24 hours at 90-95 °C. After cooling to 0°C, 500 ml of ether was added dropwise to the mixture, the precipitate formed was filtered off and dissolved in 70 ml of 40% caustic soda. The solution was extracted with 5 x 100 ml dichloromethane, dried over magnesium sulfate and evaporated in vacuo. The evaporation residue was crystallized 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

c) 3, 6, 9- tris-(carboxymethyl)- 14- thia- 3. 6, 9- triazabiscyclo f 9. 2. 11tetradeca- 1( 13). the 11th

7.5 g (35.5 mmol) of the title compound from example 17b were dissolved in 45 ml of water, 13.42 g (142 mmol) of chloroacetic acid were added and the pH was adjusted to 9.5 with 6 N potassium hydroxide. It was then heated for 12 hours at 45-50 °C, and the pH was kept at 9.5-10 by adding more potash. After cooling to 10 °C, concentrated hydrochloric acid was added to pH 2. The precipitate formed was isolated by filtration, was dissolved in 100 ml of water, and the solution was adsorbed on a cation exchange column (IR-120), the column was washed with 2 1 of water , then it was eluted with 0.5 N ammonia solution. The ammonia fraction was evaporated in vacuo, the evaporation residue was dissolved in 100 ml of water, and the solution was bound to an ion exchange column (IRA-67). The column was eluted with water and 0.5 N formic acid. From the acidic fraction, the title compound was obtained by evaporation in vacuo. For further purification, it was dissolved in methanol, and just enough acetone was added to form a precipitate. It was cooled to 0 °C, the precipitate was filtered off and 7.7 g (56.3% of theory) of the title compound were obtained as a pale 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- triazabicyclo9. 2. 11tetradeca- 1( 13). The 11-diene 2 g (5.19 mmol) of the title compound from Example 17c was heated with 941 mg (2.60 mmol) of gadolinium oxide in 20 ml of water for 4 hours at 85-90 °C. The solution was filtered and stirred successively with 0.26 g of cation exchanger (IR-120) and the same amount of anion exchanger (IRA-67). The solution was filtered again and freeze-dried. 2.66 g (95% of theory) of the title compound were obtained as a white, amorphous powder, water content 5.7%.

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

(counted as dry matter).

Example 18

a) 13- methoxy- 3. 6, 9- tris-(p- tolylsulfonyl)- 3. 6. 9. 15-tetraazabicyclo r 9. 3. llpentadeca- K15), 11, 13- triene

60.97 g (100 mmol) of N,N',N''-tris-(p-tolylsulfonyl)-diethylenetriamine-N,N''-disodium salt were dissolved in 800 ml of dimethylformamide and added dropwise at 50 °C over 90 my. 47.76 g (100 mmol) of 2,6-bis-(p-tolylsulfonyloxymethyl)-4-methoxy-pyridine dissolved in 400 ml of dimethylformamide. Stirring was continued for 5 hours at 90 °C, then 1.1 1 of water was added dropwise, the precipitate was filtered off, washed with water, the product was dried in a vacuum oven and was recrystallized from isopropyl alcohol. 43.3 g (62% of theory) of the title compound were obtained as a white powder.

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- tetraazabicyclo9. 3. 11pentadeca-1( 15). 11. The 13-triene 30 g (42.9 mmol) of the title compound from example 18a was stirred with 100 ml of concentrated sulfuric acid for 24 hours at 95 °C. After cooling to 0 °C, 400 ml of ether was added dropwise, the formed precipitate was filtered off and dissolved in 60 ml of 40% caustic soda. The solution was extracted with 5 x 75 ml dichloromethane, dried over magnesium sulfate and evaporated in vacuo. The evaporation residue was crystallized from diisopropyl ether to give 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

c) 13-Methoxy-3,6,9-tris-(carboxymethyl)-3,6,9,15-tetraazabicyclo9. 3. 11pentadeca-1(15), 11, 13-triene

6.2 g (26.2 mmol) of the title compound from example 18b was dissolved in 40 ml of water and 9.90 g (104.8 mmol) of chloroacetic acid was added. By adding 6 N potassium hydroxide, the pH was adjusted to 9.5, and the mixture was heated for 8 hours at 45-50 °C. During this time, the pH was kept at 9.5-10 by adding more potash. It was then cooled in an ice bath, and concentrated hydrochloric acid was added to pH 2. A precipitate formed, which was filtered off, the residue was dissolved under gentle heating in 80 ml of water, and the solution was adsorbed on a cation exchange column (IR-120). The column was first eluted with plenty of water, then with 0.5 N ammonia solution. The basic eluate was combined and evaporated in vacuo. The evaporation residue was dissolved in 80 ml of water, and the solution was adsorbed on an anion exchange column (IRA-67). It was eluted first with water, then with 0.5 N formic acid. The acidic fraction was evaporated in vacuo,

the residue was dissolved in methanol and was precipitated by adding acetone to the title compound. 7.42 g (69% of theory) were obtained as 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) Gadolinium complex of 13-methoxy-3.6,9-tris-(carboxymethyl)-3.6.9.15-tetraazabicyclof 9.3.11pentadeca-1(15), 11.13-triene 5 g (12, 18 mmol) of the title compound from Example 18c was heated with 2.21 g (6.09 mmol) of gadolinium oxide in 60 ml of water for 4 hours at 85-90 °C. The solution was filtered and freeze-dried. 6.74 g (98%) of the above compound was obtained as a white, amorphous powder, water content 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

(counted as dry matter).

Example 19

a) 13-chloro-3,6,9-tris-(tert.-butoxycarbonylmethyl)-3. 6. 9. 15- tetraazabicyclo9. 3. llpentadeca- K15). 11. The 13-trien

To 7 g (29.08 mmol) of the title compound from example 5c and 10.17 g (95.96 mmol) of sodium carbonate in 200 ml of acetonitrile was added 18.72 g (95.96 mmol) of bromoacetic acid tert-butyl ester, after which was stirred for 24 hours at room temperature. It was evaporated in vacuo, the evaporation residue was dissolved in 300 ml of water, and it was extracted three times with 200 ml of methylene chloride. After drying the organic phases over magnesium sulfate, the solution was evaporated in vacuo, and the remaining oil was chromatographed on silica gel (eluent: methylene chloride/ethanol = 15/1).

Yield: 14.08 g (83% of theory) of a colorless oil.

Analysis: Calculated: C 59.73, H 8.12, N 9.61, O 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-( tert.- butoxycarbonylmethyl)- 3. 6, 9. 15- tetraazabicyclo9. 3. 11pentadeca-1( 15) . 11. 13- the trien

To 13.5 g (23.15 mmol) of the title compound from Example 19a, 3.94 g (46.3 mmol) of pyrrolidinone and 612 mg (2.32 mmol) of 18-crown-6 in 200 mL of anhydrous dimethylformamide were carefully added 1.11 g (46.3 mmol) sodium hydride (previously washed with pentane). The mixture was stirred for 72 hours at 70 °C under nitrogen. The solution was cooled to room temperature and poured into 1.2 L of ice water. It was then extracted three times with 250 ml of acetic acid. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The evaporation residue was chromatographed on silica gel (eluent: methylene chloride/methanol: 13/1).

Yield: 5.7 g (39% of theory) colorless oil which crystallized on standing.

Analysis: Calculated: C 62.73, H 8.46, N 11.09, 0 17.73

Found: C 63.68, H 8.54, N 11.01

c) 13-(N-pyrrolidino)-3,6,9-tris-(carboxymethyl)-3,6.9,-15-tetraazabicyclo9. 3. llpentadeca- K15). 11, 13- the trien

5.1 g (8.07 mmol) of the title compound from example 19b was dissolved in 50 ml of trifluoroacetic acid and stirred for 6 hours at room temperature. The solvent was evaporated in vacuo and purified as described in example 1d on an anion exchange column. Crystallization from MeOH/acetone gave 2.88 g (77% of theory) of a highly hygroscopic compound.

Analysis: Calculated: C 54.42, H 6.31, N 15.11, O 24.17

Found: C 54.37, H 6.42, N 15.05

d) Gadolinium complex of 13-( N- pyrrolidino)- 3. 6, 9- tris-( carboxymethyl)- 3. 6. 9. 15- tetraazabicyclof 9. 3. 11pentadeca- 1 ( 15). 11. 13- the trien

2.5 g (5.4 mmol) of the title compound from Example 19c was dissolved in 20 ml of deionized water and 978 mg (2.7 mmol) of gadolinium oxide was added. The mixture was stirred for 3 hours at 90 °C. The solution was filtered and the filtrate freeze-dried.

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

Analysis: Calculated: C 40.83, H 4.24, N 11.34, O 18.13,

Gd 25,46

Found: C 40.74, H 4.37, N 11.28, Gd 25.41

Example 20

a) 13- azido- 3, 6, 9- tris-( tert.- butoxycarbonylmethyl) - 3. 6. 9. 15- tetraazabisvchloro9. 3. 11pentadeca-1( 15). 11. The 13-triene 21 g (36.01 mmol) of the title compound from example 19a was dissolved in 200 ml of dimethylformamide, and 7.02 g (108 mmol) of sodium azide and 951 mg (3.6 mmol) of 18-crown- 6. The mixture was stirred for 48 hours at 90 °C. After cooling to room temperature, the mixture was poured into 1.5 l of ice water, and it was extracted three times with 200 ml of acetic acid. After drying the organic phase on magnesium sulfate, it was evaporated, and the remaining oil was chromatographed on silica gel (eluent: methylene chloride/ethanol = 15/1).

Yield: 10.83 g (51% of theory) 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-( tert.- butoxycarbonylmethyl) - 3. 6. 9. 15- tetraazabicyclo f 9. 3. 11pentadeca- 1( 15). 11. The 13-triene 10 g (16.96 mmol) of the title compound from Example 20a was dissolved in 400 ml of ethanol and 1 g of Pearlman catalyst (20% palladium hydroxide on carbon) was added. After 24 hours of hydrogenation at normal pressure, the catalyst was filtered off and evaporated in vacuo. The remaining oil was chromatographed on silica gel (eluent: methylene chloride/methanol/triethylamine = 10/1/0.05). 8.89 g (93% of theory) of pale yellow oil was obtained.

Analysis: Calculated: C 61.78, H 8.76, N 12.42, 0 17.03

Found: C 61.67, H 8.91, N 12.35

c) 13- amino- 3. 6. 9- tris-(carboxymethyl)- 3, 6. 9, 15-tetraazabicyclo f 9. 3. llpentadeca- K15), 11, 13- triene

8.2 g (14.55 mmol) of the title compound from example 20b was dissolved in 100 ml of trifluoroacetic acid and was stirred for 6 hours at room temperature. After evaporating the solvent in vacuo, the residue was dissolved in 100 ml of water and placed on a column filled with poly-(4-vinyl-pyridine). After evaporation in vacuo and crystallization from methanol/acetone, 5.24 g (91% of theory) of a highly hygroscopic solid were obtained.

Analysis: Calculated: C 51.64, H 6.37, N 17.71, 0 24.28

Found: C 51.74, H 6.31, N 17.63

d) Gadolinium complex of 13- amino- 3, 6. 9- tris-( carboxymethyl )- 3, 6, 9, 15- tetraazabicyclof 9. 3. Upentadeca-1( 15) . 11. 13- the trien

4.8 g (12.14 mmol) of the title compound from Example 20c was dissolved in 35 ml of deionized water and 2.2 g (6.07 mmol) of gadolinium oxide was added. It was stirred for 3 hours at 90 °C and the pH value was maintained at 5.5 by the addition of acetic acid. The solution was filtered and placed on a column of poly-(4-vinyl-pyridine). After treatment with activated carbon, filtered again and freeze-dried.

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

Analysis: Calculated: C 37.15, H 4.06, N 12.74, O 17.47,

Gd 28,61

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

Example 21

a) 13-(hydroxyacetamido)-3,6,9-tris-(tert,-butoxycarbonylmethyl)-3,6,9,15-tetraazabicycloT9. 3. llpentadeca-1( 15). 11. 13- the trien

5.8 g (10.28 mmol) of the title compound from Example 20b, 861 mg (11.32 mmol) glycolic acid and 1.53 g (11.32 mmol) 1-hydroxy-1H-benzotriazole hydrate were dissolved in 20 ml absolute dimethylformamide and was cooled to 0 °C. 2.36 g (11.32 mmol) of dicyclohexylcarbodiimide were added, and the mixture was stirred for 1 hour at 0 °C, then overnight at room temperature. The solution was poured into 150 ml of ice water and extracted with 3 x 150 ml of acetic acid. After drying the organic phase over magnesium sulfate, it was evaporated in vacuo. The evaporation residue was chromatographed on silica gel (eluent: methylene-

chloride/methanol = 10/1).

Yield: 2.88 g (45% of theory) colorless solid.

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-tris-(carboxymethyl)-3,6,9,15-tetraazabicyclo f9. 3. 11 pentadeca- 1( 15). 11. The 13-trien

2.7 g (4.34 mmol) of the title compound from example 21a was dissolved in 40 ml of trifluoroacetic acid and stirred for 6 hours at room temperature. It was evaporated in vacuo and the residue was purified as described in example 1d on an anion exchange column. Crystallization from isopropanol gave 1.56 g (79% of theory) of 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

c) Gadolinium complex of 13-( hydroxyacetamido)- 3, 6, 9-tris-( carboxymethyl)- 3, 6, 9, 15- tetraazabicyclo f 9. 3. 11-pentadeca- 1( 15), 11, 13- triene

1.45 g (3.2 mmol) of the title compound from Example 21b was dissolved in 10 ml of deionized water and 580 mg (1.6 mmol) of gadolinium oxide was added. The mixture was stirred for 3 hours at 90 °C, the solution was filtered and the filtrate freeze-dried.

Yield: 1.94 g (100% of theory) 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-triazabischloro9. 3. 11pentadeca-1(15), 11, 13-triene

182.85 g (300 mmol) of N,N',N''-tris-(p-tolylsulfonyl)-diethylenetriamine-N,N''-disodium salt were dissolved in 2.4 L of dimethylformamide and heated to 100 °C . Over the course of 3 hours, a solution of 63.15 g (300 mmol) of 4-chloro-2,6-bis-(chloromethyl)-pyridine in dimethylformamide was added dropwise. One touched over

overnight at 100 °C. 3 1 of water were added dropwise to the still hot solution, and it was cooled to room temperature. The precipitate was washed with plenty of water and evaporated to dryness in vacuo (60 °C). Crystallization from acetonitrile gave 128.7 g ( 61% of theory) title compound as a colorless powder Analysis: Calculated: C 54.65, H 5.02, N 7.97, O 13.65,

S 13.68, Cl 5.04

Found: C 54.61, H 5.13, N 7.91, S 13.65,

Cl 5.09

b) 13-(N-morpholino)-3,6,9-tris-(p-tolylsulfonyl)-3,6,9-triazabicyclo9. 3. 11pentadeca-1( 15). 11. 13- the trien

126 g (179 mmol) of the title compound from example 22a was dissolved in 500 ml of dimethyl sulfoxide and 87.12 g (1 mol) of morpholine was added. The solution was stirred in an autoclave for 48 hours at 140 °C and 10 bar. It was cooled, poured into 3 1 of ice water and the precipitate filtered off. After drying in vacuum at 60 °C, it was recrystallized from acetone. 87.72 g (65% of theory) of cream-colored powder was obtained.

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-morpholino)-3.6,9,15-tetraazabicyclo r9. 3. llpentadeca- K 15). 11. The 13-triene 86 g (114 mmol) of the title compound from example 22b was added to 270 ml of concentrated sulfuric acid and stirred for 48 hours at 100 °C. It was cooled to 0°C and 1.35 1 absolute ether was added dropwise. The precipitate was filtered off and suspended in 100 ml of aqueous caustic soda (pH 12). It was extracted seven times with 150 ml of chloroform and the combined organic phases were dried over magnesium sulphate. After evaporation in vacuo, 22.26 g (67% of theory) of yellowish oil was obtained which crystallized on standing.

Analysis: Calculated: C 61.82, H 8.65, N 24.04, O 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-tetraazabicyclo9♦ 3. llpentadeca- K15). 11, 13-triene 10 g (34.3 mmol) of the title compound from example 22c was dissolved in 150 ml of water and 12.85 g (136 mmol) of chloroacetic acid was added. The pH was adjusted to 9.5 with 6 N potassium hydroxide. It was stirred for 12 hours at 45 °C, and the pH value was maintained at 9.5-10 by the addition of 6 N potassium hydroxide. It was adjusted to pH 2 with concentrated hydrochloric acid, and purified on ion exchangers as described in example ld. Crystallization from methanol/acetone gave 9.9 g (62% of theory) of the title compound as a highly hygroscopic solid.

Analysis: Calculated: C 54.18, H 6.71, N 15.05, O 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-tetraazabicyclo9. 3. 11-pentadeca-1(15), 11, 13-triene 9 g (19.33 mmol) of the title compound from example 22d was dissolved in 60 ml of deionized water and 3.5 g (9.67 mmol) of gadolinium oxide was added. The mixture was stirred for 3 hours at 90 °C and the pH value was maintained at 5.5 by adding acetic acid. The solution was filtered and placed on a column filled with poly-(4-vinyl-pyridine). After treatment with activated charcoal, it was filtered again and freeze-dried.

Yield: 10.9 g (91% of theory) of an amorphous powder which, according to analysis, contains 9.87% water.

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-f9. 3. llpentadeca- K15), 11, 13- triene

9.3 g (38.62 mmol) of the title compound from Example 5c and 21.36 g (154.5 mmol) of potassium carbonate were dissolved in 200 ml of dimethylformamide and heated to 70 °C. Within 30 min. 26.43 g (154.5 mmol) of benzyl bromide was added dropwise, and the mixture was stirred for 24 hours at 70 °C. The solvents were evaporated in vacuo, and the evaporation residue was taken up in 250 ml of 3 N caustic soda. It was extracted five times with 150 ml of methylene chloride, and the organic phases were dried over magnesium sulphate. After evaporation in a vacuum, it was chromatographed on silica gel (eluent: isopropanol/triethylamine = 20:1).

Yield: 17.97 g (91% of theory) 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-carboxyl-3,6,9-tris-(benzyl)-3,6,9,15-tetraazabischloro9. 3. llpentadeca- K15), 11, 13- triene

A solution of 17.5 g (34.24 mmol) of the title compound from example 23a in 80 ml of 1,2-dimethoxyethane was added dropwise to 1.95 g (79.44 mmol) of magnesium shavings and the mixture was heated to boiling. A solution of 6.43 g (34.24 mmol) of 1,2-dibromoethane in 40 ml of 1,2-dimethoxyethane was then added dropwise over the course of 12 hours. It was cooled in an ice bath and the solution was carefully poured onto 10 g of dry ice. After stirring for 3 hours at room temperature, 200 ml of water was carefully added, and the pH was adjusted to 4 with hydrochloric acid. It was evaporated to dryness and the residue was boiled with 200 ml of ethanol. After filtering off the magnesium salt was evaporated again to dryness, and the residue was chromatographed on silica gel (eluent: chloroform/methanol/triethylamine = 20/15/1).

Yield: 5.16 (29% of theory) pale yellow solid.

Analysis: Calculated: C 76.27, H 6.79, N 10.78, O 6.16

Found: C 76.19, H 6.88, N 10.71

c) 13-(morpholinocarbonyl)- 3, 6, 9- tris-( benzyl)- 3, 6, 9, 15-tetraazabicyclo f 9. 3. llpentadeca- K15), 11, 13- triene

5.0 g (9.62 mmol) of the title compound from Example 23b, 922 mg (10.58 mmol) of morpholine and 1.43 g (10.58 mmol) of 1-hydroxy-1H-benzotriazole hydrate were dissolved in 10 ml of absolute dimethylformamide and cooled to 0 °C. 2.18 g (10.58 mmol) of dicyclohexylcarbodiimide were added, and the mixture was stirred for 1 hour at 0 °C, then overnight at room temperature. The solution was poured into 180 ml of ice water and extracted three times with 150 ml of chloroform. After drying the organic phase on magnesium sulfate, it was evaporated in vacuo. The evaporation residue

was chromatographed on silica gel (eluent: chloroform/methanol/triethylamine = 20/5/1).

4.22 g (88% of theory) of the title compound were obtained as 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-tetraazabiscyclo-T9. 3. 11pentadeca-1(15), 11, 13-triene

4.1 g (6.96 mmol) of the title compound from Example 23c was dissolved in 250 ml of ethanol and 0.5 g of Pearlman catalyst (20% palladium hydroxide on charcoal) was added. After 24 hours of hydrogenation in an autoclave (50 °C and 3 bar hydrogen pressure), the catalyst was filtered off and evaporated in a vacuum. The evaporation residue was 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

e) 13-(morpholinocarbonyl)-3,6,9-tris-(carboxymethyl)-3,6,9,15-tetraazabischloro9. 3. llpentadeca- K15). 11. The 13-trien

1.6 g (5.0 mmol) of the title compound from Example

23d was dissolved in 25 ml of water and 1.89 g (20 mmol) of chloroacetic acid was added. The pH was adjusted to 9.5 with 6 N potassium hydroxide. The mixture was stirred for 12 hours at 45 °C, and the pH value was maintained at 9.5-10 by the addition of 6 N potassium hydroxide. After work-up on ion exchange columns as in example 1d, after crystallization from methanol/acetone 1.66 g (67% of theoretical) highly hygroscopic solid was obtained.

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 ) Gadolinium complex of 13-(morpholinocarbonyl)-3.6,9-tris-(carboxymethyl)-3,6,9,15-tetraazabicyclo 9.3.11-pentadeca-K15),11,13-triene

1.5 g (3.04 mmol) of the title compound from example 23e was dissolved in 10 ml of deionized water and added 551 mg

(1.52 mmol) of gadolinium oxide. The mixture was stirred for 3 hours at 90 °C. The solution was filtered and the filtrate freeze-dried.

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

Analysis: 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 of NMR diagnostics in vivo

A nude mouse Balb/c, nu/nu, female, 20 g, with subcutaneous colon carcinoma HT 29 was after a prior recording in a nuclear spin tomograph (supplier: General Electric, 2 tesla) introduced a gadolinium complex of 3,6,9-tris-(carboxymethyl) -3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (example le) per kg i.v. through a cauda elven. The compound was dissolved in double distilled water (pH 7.2). Recordings were made using a spin-echo sequence, TR = 400 msec., TE = 30 msec. The recordings were made before, as well as 1, 23 and 43 min. after the introduction of contrast medium in the area around the liver and tumor. It could be shown that the signal intensity of the tumor rose and did not fall during the examination period.

The illustration shows a nude mouse Balb/c, nu/nu with colon carcinoma HT 29 as a transverse section before and after intravenous administration of contrast medium. The recordings were made by spin-echo sequence, TR = 400 msec., TE = 30 msec.

On the left above, the mouse can be seen before contrast medium introduction

Eng. The recording shows the liver and the subcutaneous tumor. The other recordings were made 1, 23 and 43 min. after the introduction.

Claims (4)

1. Macrocyclic compound for use as NMR-, X-ray or radiodiagnostic means, characterized in that it has a structure as indicated by the general formula I where - - - - denotes a single or double bond, q denotes a number that is 0 or 1, A and B, which may be the same or different, each denote a straight-chain or branched alkylene group with 2-6 C atoms, D denotes a nitrogen or oxygen atom, the group =C=0, =NR<2> with R<2> in the sense of a hydrogen atom or a C1-C6 alkyl group, the group with R3 in the sense of a hydrogen or halogen atom, a phenyl, a C1-C6 alkyl group which is optionally substituted with one or more phenyl and/or hydroxy groups, the residue OR<5>, where R<5> denotes a C1- C6-alkyl radical which is optionally substituted with 1-3 hydroxy groups; the substituent where 1 denotes the number 0 or 1, and R5 and R7 independently of each other denote hydrogen atoms, the residue R<5> or phenyl or benzyl residues optionally substituted with 1-3 hydroxy groups, or R<6> and R7 together with the nitrogen atom denote a saturated or unsaturated 5- or 6- ring which optionally contains a further nitrogen atom, oxygen atom, sulfur atom or a carbonyl group and is optionally substituted with 1-3 residues R<5>, or one of the substituents R<6> or R<7> stands for the rest or denotes the substituent G, where G denotes a second macroring of general formula II which is bound via a direct bond, a bis(carbonylamino) group (-NH-CO-CO-NH-) or via a C1-C20 alkylene group which optionally carries a carbonyl-(>C0)-, a carbonylamino(- NH-CO-) group or oxygen atoms and which optionally contains one or more oxygen atoms, Z-, acyl- or hydroxyacyl-substituted imino groups or one or two C-C double and/or C-C triple bonds, where D<1> has the same meaning as D except that D<1> does not contains the substituent G or denotes the residue F<1> has the same meaning as F except that F<1> does not contains the substituent G, or denotes the residue or E denotes a nitrogen, sulfur or oxygen atom, the groups or >NR<4> where R<4> has meaning the formation of a hydroxy group, R or an optionally hydroxylated or carboxylated C^Cg alkyl group, F denotes -(CHR<8->)n or (=CR<8->)n where n denotes 0 or 1, and R<8> has the meaning R<1> or G, R<1> denotes a hydrogen or halogen atom or a C\- C6 alkyl group, Z denotes a hydrogen atom or the group -CH2COOY where Y denotes a hydrogen atom and/or a metal ion equivalent of an element with 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 denote the residue -CH2COOY, while at least two of the substituents Y denote metal ion equivalents of at least one element with atomic numbers 21-29, 42, 44 or 57-83 or at least one radionuclide of an element with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77, and the macrocyclic compound of general formula I does not contain more than one residue G, and with the proviso that the compound is not Cu-, Pb -, Co or Sr complex of 3, 6, 9,15-tetraazabicyclo[9.3.l]pentadeca-1(15), 11,13-triene-N-triacetic acid, as well as its salts with inorganic and/or organic bases, amino acids or amino acid amides. 2. Compound according to claim 1, characterized in that G denotes a ring of general formula II which is bound via a group selected from 3. Diagnostic preparation, characterized in that it contains at least one compound according to claims 1-2, possibly together with common medical additives. 4. Use of at least one physiologically acceptable compound according to claim 3 for the production of an agent for NMR, X-ray or radio diagnostics.