IE66693B1 - Macrocyclic polyaza compounds containing 5 or 6 rings process for producing them and pharmaceutical media containing them - 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 invention relates to the subject characterised in the patent claims, that is to say to macrocyclic polyaza complexing agents, complexes and complex salts containing a 5- or 6-membered ring, to agents containing those compounds, to their use as diagnostic and therapeutic agents, and to processes for the preparation of those compounds and agents.

Metal complexes were considered as contrast agents for radiology as early as the beginning of the 1950s.

However, the compounds used at that time were so toxic that there was no question of their being used in humans. It was therefore completely surprising that certain complex salts have proved to be sufficiently tolerable that routine use thereof in humans for diagnostic purposes could be considered. As the foremost representative of this class of substances, the dimeglumine salt of Gd DTPA (gadolinium(III) complex of diethylenetriaminepentaacetic acid), which is described in the European Patent Application having the publication number 71564, has proved very successful as a contrast agent for nuclear spin tomography in clinical trials on over 7000 patients. The main area of application is in disorders of the central nervous system.

A fundamental reason for the good tolerability of Gd DTPA in clinical use is.its high degree of effectiveness in nuclear spin tomography, especially in th© case of many brain tumours. Because of its good effectiveness, Gd DTPA can be used in much lower doses, at 0.1 mmol/kg of body weight, than, for example, X-ray contrast agents in many X-ray examinations.

As a further representative of the complex salts, the meglumine salt of Gd DOTA (gadolinium(XXI) complex of 1,4,7,10-tetraasacyclododecanetetraacetic acid), which is described in German Patent Application 34 01 052, has proved suitable for diagnostic purposes.

However, it is now desired to use chelates at even higher doses. That is the case especially for detecting certain disorders outside the central nervous system with the aid of nuclear spin tomography (NMR diagnostics), but most especially in the use of chelates as X-ray contrast agents.

In order to keep the volume loading of the body as low as 10 possible, it is necessary to use highly concentrated chelate solutions. The chelates hitherto known are not very suitable for that purpose especially on account of their too high osmolality.

There is therefore a need for chelates that have a lower 15 osmolality than do the prior-known chelates. At the same time, however, the requirements for use of those compounds in humans as regards the gap between the effective dose and the dose that is toxic in animal tests (the therapeutic range), the organ specificity, the stability, the contrast-heightening effect, the tolerability and the solubility of the complex compounds must be fulfilled.

The problem underlying the invention is, therefore, to make those compounds and agents available, and to provide a process for their preparation that is as simple as possible.

This problem is solved by the present invention.

The complex compounds according to the invention and the solutions prepared therefrom fulfil the mentioned requirements in a surprising manner. They possess a reduced osmolality as well as a more advantageous therapeutic range and/or stability and storability of the chemical constituents of the solution and/or organ specificity and/or contrast-heightening effect (e.g. relaxivity) and/or tolerability (e.g. fewer cardiovascular or allergic side-effects) than do the hitherto conventional diagnostic agents.

Even without specific measures, their pharmacokinetics permits improved diagnosis of numerous disorders. The complexes are for the most part excreted rapidly and in unchanged form, so that no harmful effects are observed despite the high doses employed, in particular, even when relatively toxic metal ions are used.

The practical use of the novel complexes and complexing agents is also facilitated by their advantageous chemical stability.

A further fundamental advantage of the described complexes and complexing agents is their extraordinary chemical versatility. In addition to the central atom, the selection of a variety of substituents, of the 5- or 6-membered ring in the macrocycle and/or of the saltforming substances allows the properties to be adapted to requirements as regards effectiveness, pharmacokinetics, tolerability, solubility, handling, etc.. For example, it is possible to achieve specificity of the compounds for structures in the organism, for particular biochemical substances, for metabolic processes, or for conditions of the tissues or body fluids, which is highly desirable in diagnostics and therapy.

The macrocyclic compounds according to the invention are characterised by the general formula I: wherein represents a single bond or a double bond, q represents the numbers 0 to 5, A and B, which are the same or different, each represent a straight-chained or branched alkylene group having from 2 to 6 carbon atoms, D represents a nitrogen atom, an oxygen atom, the group —C=Q, =NR2, -CER3- or =CR3-, 10 E represents a nitrogen atom, a sulphur atom, an oxygen atom, the group =h(+)-, =C- or >NR4, OH, P represents (~CHRs-)n or (=CR8)n, R1 represents a hydrogen atom or a halogen atom or a Cx-C6-alkyl group, Z represents a hydrogen atom or the group -CHjCOOY wherein Y represents 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, R2 represents a hydrogen atom or a Ci-Cg-alkyl group, R3 represents a hydrogen atom or a halogen atom, a phenyl group or a C^-Cg-alkyl group optionally substituted by one or more phenyl and/or hydroxy groups, or represents the radical OR®, the substituent -(C)yNRsR7 or O the substituent G, R4 represents a hydroxy group, R2 or an optionally hydroxylated or carboxylated Cj-Cg-alkyl group, R5 represents a Ci«-C6-alkyl radical optionally substituted by fro· 1 to 3 hydroxy groups.

R6 and R7, independently of each other, represent hydrogen atoms, the radical R5, or phenyl or benzyl radicals optionally substituted by from 1 to 3 hydroxy groups, or R6 and R7, together with the nitrogen atom, form a saturated or unsaturated 5- or δ-raembered ring that optionally contains a further nitrogen, oxygen or sulphur atom or a carbonyl group and that is optionally substituted by from 1 to 3 radicals R5, or one of the substituents R® and R7 represents the radical -C~R5, R8 represents R* or G, represents the number 0 or 1, n represents the number 0 or 1, G represents a second macrocycle of the general formula XI that is bonded via a direct bond, a bis(carbonylamino) group (-NH-CO-CO-NH-) or via a C1-C2Q-alkvlene group that optionally carries carbonyl (>CO) or carbonylamino (-NH-CO-) groups or oxygen atoms at the ends and that optionally contains one or more oxygen atoms, S~, acyl- or hydroxvacyl-substituted imino groups or one or two C-C-double and/or C-C-triple bonds: Z-n N(II) ΊΝ-Ξ1 wherein D1 has the same meaning as D, except that D1 does not contain the substituent G, or D1 represents the III radxcal -CH-, =C- or -N-, and F1 has the same meaning as F, except that F1 does not contain the substituent G, or F1 represents the ? 25 radical -CH- or and their salts with inorganic and/or organic bases, amino acids or amino acid amides, with the provisos that at least two of the substituents Z represent the radical -CH2C°°^» that the macrocvclic compound of the general formula I does not contain more than one radical G, and that the general formula I does not represent 3,6,9,12,18-pentaa2abicyclo[12.3.1]octadeca~l(18),14,16-triene-N-tetraacetic acid or 3,6,9,15tetraazabicyclo[ 9.3.l]pentadeca-l (15), 11,13-triene-Ntriacetic acid or their Cu, Pb, Co and Sr complexes.

When n is the number 0 and the 5-membered ring so formed is to be unsaturated, then the double bonds are located between positions 2,3 and 4,5 of the 5-membered ring.

Compounds of the general formula I wherein Y represents hydrogen are called complexing agents, and those wherein at least two of the substituents Y represent a metal ion equivalent are called metal complexes.

Of course, the element of the above-mentioned atomic number, which forms the central ion of the physiologically tolerable complex salt, may, for the intended use of the diagnostic agent according to the invention, also be radioactive.

If the agent according to the invention is intended for use in NMR diagnostics, the central ion of the complex salt must be paramagnetic. Paramagnetic ions are especially the di- and tri-valent ions of the elements of atomic numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example, the chromium(III), manganese(II), iron(II), cobalt(II), nickel (II), copper (II)., praseodym(III), neodya(III), samarium(III) and ytterbium (I II) ions. The gadolinium(III), terbium(III), dysprosium» (III), holmium(III), erbium(III) and iron(Iix) ions are especially preferred on account of their very strong magnetic moment.

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

If the agent according to the invention is to be used in X-ray diagnostics, then the central ion must be derived from an element having a relatively high atomic number in order to achieve adequate absorption of the X-rays. It 15 has been found that diagnostic agents containing a physiologically tolerable complex salt having central ions of elements of atomic numbers 21-29, 42, 44, 57-83 are suitable for that purpose; such ions are, for example, the lanthanum(III) ion and the above-mentioned 2o ions of the lanthanide series.

Suitable alkyl substituents R1, R2, R3 and R4 are straight-chained or branched hydrocarbons having up to 6, preferably up to 4, carbon atoms, which are optionally substituted in the case of R3 by one or more, preferably from 1 to 3, phenyl and/or hydroxy groups, in the case of R4 by one or more, preferably from 1 to 3, hydroxy or carboxy groups, and in the case of R5 by one or more, preferably from 1 to 3, hydroxy groups.

There may be mentioned as optionally substituted alkyl groups, for example, the groups methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-hydroxy-x-(hydroxymethyl)-ethyl, 1-(hydroxymethyl)-ethyl, propyl, isopropyl, 2- and 33 hydroxypropyl, 2,3-dihydroxypropyl , η-, sec.- and tert.butyl, 2-, 3- and 4-hydroxybutyl, 2- and 3-hvdroxyisobutyl, pentyl, 2-, 3- and 4-hydroxy-2-methylbutyl, 2,3,4trihydroxybutyl, l,2,4-trihydroxybutyl, cyclopentyl, cyclohexyl, 2,3,4,5,6-pentahydroxyhexyl, benzyl, carboxymethyl and carboxyethyl.

There may be mentioned as a halogen atom contained in Rand R3 fluorine, chlorine, bromine and iodine.

The heterocyclic 5- or S-raembered ring formed by R° and R7 with the inclusion of the nitrogen atom may be saturated, unsaturated and/or substituted and may contain a nitrogen atom, an oxygen atom, a sulphur atom or a carbonyl group.

There may be mentioned as examples of suitable heterocycles: the pvrrolidinyl, piperidyl, pyrazolidinyl, pyrrolinyl, pyrazolinyl, piperazinyl, morpholinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl and pyrrolidonyl rings.

Suitable alkylene groups A and B are straight-chained or branched chains having from 2 to 6 carbon atoms, preferably the ethylene, methylethylene and propylene groups.

The alkylene chain to which the second macrocycle XI is bonded optionally carries carbonyl (CO) or carbonylamino (MH-CG) groups or oxygen atoms at the ends and contains from l to 20 carbon atoms. It may be interrupted by one or more oxygen atoms, Z-, acyl- or hydroxyacylsubstituted imino groups or one or two C-C-double and/or C-C-triple bonds. However, the two macrocycles may also be linked by means of a direct bond. Suitable optionally hydroxylated acyl groups are acyl radicals having up to 10 carbon atoms. The acetyl, propionyl, butyryl, benzoyl and hydroxyacetyl radicals may be mentioned by way of example.

The alkylene chain may be straight- or branched-chained, saturated, or unsaturated, and may be interrupted as described. It may contain up to 4 oxygen atoms and/or up to 3 carboxymethylimino groups.

Examples of the alkylene chain are: -(ch2i2-, -ch2-o-ch2-, -2ifs-, -(ch2~ch2-o-ch2-ch2)-, -(ch2-o-ch2i -(CH2-O-CH2)3-, -CH2-CH2-(O-CH2~CH2)3-, -CH2-CH2~(O-CH2-CH2)t-, -CH., -CH I OH OH I CH-CH-, -CH -C-. il 2 I OH OH ch2-cooh CH_-CH-CH-CH„-, -C=C-C=C-, -NH-C-(CH,)n -< 2 | | a i 0-5 OK OH -NH •CH.-M-CH -CH,-N-CH -CH -N-CH?-, 2 | 2 ί | ί <| 0 II n -C-(CH2J 1 _g-C-, o-(ch2):-5-0-.

|CH2 COOH ch2 COOH |CH2 COOH CH -H~CH_- , CO-CHjOH 2)2ch=ch-(ch2)215 If not all acidic hydrogen atoms are substituted by the 10 central ion, it is possible for one, more than one or all of the remaining hydrogen atoms to be replaced by cations of inorganic and/or organic bases or of amino acids. Suitable inorganic cations are, for example, the lithium ion, the potassium ion, the calcium ion, the magnesium ion and, especially, the sodium ion. Suitable cations of organic bases are inter alia,, cations of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine and, especially, Nmethylglucaraine. Suitable cations of amino acids are, for example, cations of lysine, arginine and ornithine.

The macrocyclic complexes of the general formula I according to the invention are prepared as follows: compounds of the general formula I* H-N I A N-H (I') , (N-91 wherein X represents or a 5 or 6-membered ring for :F conversion into the desired ring, are alkylated in a manner known per se with a halogen compound III KalCH2CQQY? (III), wherein Hal represents chlorine, bromine or iodine and Y' represents a hydrogen atom or an acid-protecting group, and then, where appropriate after conversion of X into the desired 5- or 6-membered ring of the end product and, where appropriate, after removal of the protecting groups Y‘?, the resulting complexing agents of the general formula I wherein Y represents hydrogen ar®, if desired, reacted in a manner known per se with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83 and then, if desired, any acidic hydrogen atoms that are still present are replaced with cations of inorganic and/or organic bases, amino acids or amino acid amides.

Suitable acid-protecting groups Y' are lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, n-butyl, tert.-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl and bis (p-nitrophenyl)methyl groups, as well as trialkyIsilyl groups.

The removal of the protecting groups ¥·', which may be carried out before or after the conversion of X into the desired 5- or 6-membered, ring of the end product, is effected according to the processes known to the person skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline hydrolysis of the esters with alkali in aqueous-alcoholic solution at temperatures of from 0 to 50c or, in the case of, for example, tert.-butyl esters, with the aid of trifluoroacetic acid.

The alkylation of the starting materials If with the halogen compounds of the general formula III is carried out in polar aprotic solvents such as, for example, dimethylformamide, acetonitrile, dimethyl sulphoxide, aqueous tetrahydrofuran or hexamechylphosphoric acid triamide in the presence of an acid acceptor, such as, for example, a tertiary amine (e.g. triethylamine, triraethylamina, Ν,Ν-diaethylaminopyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,5-diazabicyclo[5.4.0]undec-5~ ene (DBU)), an alkali metal or alkaline earth metal carbonate, hydrogen carbonate or hydroxide (e.g. sodium, magnesium, calcium, barium and potassium carbonate, hydroxide and hydrogen carbonate) at temperatures of from —10"C to 120"c, preferably from O’C to 50’c.

The conversion of a precursor of the desired 5- or 6membered ring contained in the end product is carried out according t© the methods known to the person skilled in the art. There may be mentioned by way of example the hydrogenation of, for example, pyridine rings [Advan. Catal. 14 . 203 (19.63)], pyrrole rings [M. Freifelder, Practical Catalytic Hydrogenation, 577, Wiley-Inter5 science, Mew York-London-Sydney-Toronto 1971], furan rings [US-3,194,818] and pyrimidine rings [J. Med. Chem. 15. 291 (1972)], the deoxygenation of nitroxide rings [E. Klingsberg, The Chemistry of Heterocyclic Compounds, Volume 14, part 2, Interscience Publishers New York, IQ p. 120 (1961)], the conversion and introduction of functional groups at the 5- or 6-membered ring, for example liberation of phenolic hydroxy groups [J. Org. Chem. 53., 5 (1988)], the introduction of halogen substituents [E. Klingsberg, The Chemistry of Heterocyclic Compounds, Volume 14, Part 2, Interscience Publishers Mew York, p. 341 (1961), Houben-Weyl, Methoden der organischen Chemie, Volume V/3, 651 (1962)], the exchange of hetero atoms, for example the conversion of a furan into a pyrrole (US-2,478,456).

The functionalisation of 4-chloropyridine derivatives (e.g. azide exchange) in the phase transfer process using 18-crown-6 or tetrabutyl ammonium bromide as catalyst is described in ’’Phase Transfer Reactions (Fluka Compendium Vol. 2,- Walter E. Keller, Georg Thieme Verlag Stuttgart, Mew York).

The preparation of amides, that is to say of compounds of th© general formula I wherein R3 represents -C-MR6R7, is O effected by reacting activated acid derivatives (e.g. mixed anhydride, acid chloride) with primary or secondary amines of the general formula ^R7 wherein R6 and R7 have the meaning given above.

There may be mentioned as examples of suitable amines: dimethvlamine, diethylamine, di-n-propylamine, diisopropylamine , di-n-butylamine, diisobutylamine„ di-sec.butvlamine, N-methyl-n-propylamine, dioctvlamine, dicyclohexvlamine, N-ethylcyclohexylamine, diisopropenylamine, benzylamine, aniline, 4-methoxyaniline, 4-dimethylaminoaniline, 3,5-dimethoxyaniline, morpholine, pyrrolidine, piperidine, N-methylpiperazine, N-ethylpiperazine, N-(2-hvdroxyethyl)-piperazine, (hydroxymethyl) -piperazine, 2-(2-hydroxymethvl)-piperidine, 4-(2hydroxyethvT)-piperidine, 2-hydroxymethylpiperidine, 4hydroxymethylpiperidine, 2-hydroxymethylpyrrolidine, 3hydroxypiperidine, 4-hvdroxypiperidine, 3-hydroxypyrrolidine, 4-piperidone, 3~pvrroline, 2,6-dimethylpiperidine, 2,6-dimethylmorpholine, pyrazoline, imidazoline, oxazolidine, thiazolidine, 2,3-dihydroxypropylamine, Nmethy1-2,3-dihydroxypropylamine, 2-hydroxy-l-(hydroxymethyl )ethvlamine, N,N-bis(2-hydroxyethyl) amine, Nmethyl-2,3,4,5,6-pentahydroxyhexylamine, S-amino-2,2dimethyl-l,3-dioxepin-5-ol, 2-hydroxyethylamine, 2-amino1,3-propanediol, diethanolamine, ethanolamine.

The polyhydroxyalkylamines may advantageously also be used in the reaction in protected form, for example in the form of O-acyl derivatives or in the form of ketals. That is the case especially when those derivatives can be prepared more easily and less expensively than the polyhydroxyalkylamines themselves. A typical example is 2-aaino-l-(2,2-dimethyl-l»3-dioxolan-4-yl)-ethanol, the acetonide of i-amino-2,3,4~trihydroxybutane, prepared according to DE-OS 31 50 917.

The subsequent removal of the protecting groups is problem-free and can be carried out, for example, by treatment with an acidic ion exchanger in aqueous5 ethanolic solution.

The synthesis of compounds having more than one ring is effected according to processes known in the literature, for example via an addition/eliraination reaction of an amine with a carbonyl compound (for example acid 10 chloride, mixed anhydride, activated ester, aldehyde); of two amine-substituted rings with a dicarbonyl compound (for example oxalyl chloride, glutardialdehyde); of two p-nitro-substituted nitroxides with bisalcoholates [see E. Klingsberg, The Chemistry of Heterocyclic Compounds, Interscience Publishers New York, p. 514 (1961)]; of two rings, each of which contains a nucleophilic group, with an alkylene compound carrying two leaving groups or, in the case of terminal acetylenes, by oxidative coupling (Cadiot, Chodkiewicz in viehe ’’Acetylenes", 597-647, Marcel Dekker, New York, 1969).

The chain linking the rings can then be modified by subsequent reactions (for example hydrogenation).

The synthesis of the starting materials of the general formula I' that are to be alkylated is carried out by cyclisation of two reagents, one of which contains the substituent X, that is to say the desired 5- or Smembered ring of the end product or a precursor for conversion into that ring.

The cyclisation is carried out according to methods known in the literature (for example Org. Synth- 86 (1978), Macrocyclic Polyether Syntheses, springer Verlag Berlin, Heidelberg, New York 1982, Coord. Chem. Rev. a, 3 (1968), Ann. Chem. 1976 : 916, J. Org. Chem. 41, no [1984]): one of the two reagents carries two leaving groups at the chain end, the other carries two nitrogen atoms which 5 displace those leaving groups in a nucleophilic manner.

There may be mentioned by way of example the reaction of terminal dichloro-, dibromo-, dimesyloxy-, ditosyloxv- or dialkoxycarbonyl-alkylene compounds containing the substituent X and, optionally, from one to five nitrogen atoms, with terminal diazaalkylene compounds optionally containing from one to five additional nitrogen atoms in the alkylene chain. The substituent X may instead be contained in the second reagent, that is to say in the reagent containing the terminal nucleophilic nitrogen atoms. The nitrogen atoms are optionally protected, for example in the form of tosylates or trifluoroacetates, and are freed before the subsequent alkylation reaction by processes known in the literature (the tosylates are freed, for example, with mineral acids, alkali metals in liquid ammonia, hydrobromic acid and phenol, RedAl^^, lithium aluminium hydride, sodium amalgam, see, for example, Liebigs Ann. Chem. 1977, 1344, Tetrahedron Letters 1976, 3477; the trifluoroacetates are freed, for example, with mineral acids or ammonia in methanol, see, for example, Tetrahedron Letters 1967, 289).

For the preparation of macrocycles that are substituted at the nitrogen atoms by different substituents (hydrogen or the group CK2COQY), those atoms may be provided in the starting materials with different protecting groups, for 30 example with tosylate and benzyl groups. The latter are then likewise removed by methods known in the literature (preferably by hydrogenation, for example EP Patent Application 232751).

If diesters are used in the cyclisation reaction, the resulting diketo compounds must toe reduced according to processes known to the person skilled in the art, for example with diborane.

It is also possible to cyclise appropriately substituted terminal bisaldehydes with the terminal bisaaines desired in each particular case; the reduction of the resulting Schiff's bases is carried out according to methods known in the literature, for example by means of catalytic hydrogenation [Helv. chim. Acta 6,1, 1376 (1978) ].

The amines required as starting materials for the cyclisation are prepared analogously to methods known in the literature.

Using an M-protected amino acid as starting material, reaction with a partially protected diamine (for example according to the carbodiimide method), removal of the protecting groups and diborane reduction yield a triamine .

The reaction of a diamine obtainable from amino acids [Eur. J. Med. Chem. - Chim. Ther. 21 f 333 (1986K with twice the molar amount of an N-protected o-as.ino acid yields, after suitable working up, a tetramine.

The desired diamines can also be prepared by Gabriel reaction from, for example, the appropriate tosylates or halides [see, for example, Inorg. Chem. 35, 47.91 (1986)].

In both cases, the number of carbon atoms between the Matoms can be fixed by the nature of the diamines or amino acids used as coupling partner.

The resulting compounds of the general formula I 'wherein Y represents a hydrogen atom are complexing agents- They can be isolated and purified or can be converted, without being isolated, into metal complexes of the general formula I wherein at least two of the substituents Y represent a metal ion equivalent.

The metal complexes according to the invention are prepared in the manner disclosed in. Patent Specification DE-OS 34 01 052, by dissolving or suspending the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulphate) of the element of 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 the solution or suspension of the equivalent amount of the complex-forming acid of the general formula X wherein Y represents a hydrogen l5 atom, preferably at temperatures of from 40 to 100°C, and then, if desired, replacing any acidic hydrogen atoms of acid groups that are present with cations of inorganic and/or organic bases, amino acids or amino acid amides.

Neutralisation is carried out with the aid of inorganic bases (for example hydroxides, carbonates or hydrogen carbonates) of, for example, sodium, potassium, lithium, magnesium or calcium and/or organic bases such as inter alia primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N25 methyl- and Ν,Ν-dimethyl-glucamine, and basic amino acids, such as, for example, lysine, arginine and ornithine.

For the preparation of the neutral complex compounds it is possible, for example, to add to the acidic complex 3Q salts in aqueous solution or suspension such an amount of the desired bases that the neutral point is reached. The resulting solution can then be concentrated to dryness in vacuo. It is frequently advantageous to precipitate the resulting neutral salts by the addition of water-miscible solvents, such as, for example, lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.) and polar ethers (tetrahvdrofuran, dioxane, 1,25 dimethoxyethane, etc.) and so obtain crystals that can readily be isolated and purified. It has proved especially advantageous to add th® desired base to the reaction mixture during the complex formation, thus eliminating one process step.

If the acidic complex compounds contain several free acidic groups, it is often advantageous to prepare neutral mixed salts which contain both inorganic and organic cations as counter-ions.

This may be achieved, for example, by reacting the 1 5 complex-forming acid in aqueous suspension or solution with the oxide or salt of the element supplying the central ion and with half the amount of an organic base required for neutralisation, isolating the resulting complex salt, purifying it, if desired, and then adding 20 the amount of inorganic base necessary for complete neutralisation. The order in which the bases are added may also be reversed.

Where complex compounds containing radioisotopes are used, they may be prepared according to the methods described in Radiotracers for Medical Applications, Volume 1, CRC-Press, Boca Raton, Florida.

The pharmaceutical agents according to the invention are also prepared in a Banner known per se, toy suspending or dissolving the complex compounds according to the invention in an aqueous Bedium - optionally with the addition of additives customary in galenic pharmacy and then optionally sterilising the suspension or solution. Suitable additives are, for example, physiologically acceptable buffers (such as, for example, tromethamine), small amounts of complexing agents (such as, for example, diethylenetriaminepentaacetic acid) or, if necessary, electrolytes such as, for example, sodium chloride or, if necessary, antioxidants such as, for example, ascorbic acid.

If suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral administration or for other purposes, they are mixed with one or more adjuncts (for example methvlcellulose, lactose, mannitol) and/or surfactants (for example lecithins, Tween(, Myrj(R^) and/or taste-correcting flavourings (for example ethereal oils) customary in galenic pharmacy.

In principle, it is also possible to prepare the pharmaceutical agents according to the invention without isolating the complex salts. In that case, special care must be taken to carry out the chelate formation in such a manner that the salts and salt solutions according to the invention are virtually free of non-complexed toxic metal ions.

This can be ensured, for example, with the aid of colour indicators such as xylenol orange by means of control titrations during the preparation process. Accordingly, the invention relates also to processes for the preparation of the complex compounds and their salts. A final safety measure is purification of the isolated complex salt.

The pharmaceutical agents according to the invention preferably contain from 2. pmol to 1 mol/1 of the complex salt and are generally administered in amounts of from - 20 0.001 to 5 mmol/kg. They are intended for enteral and parenteral administration. The complex compounds according to the invention are used 1. for NMR and X-ray diagnostics in the form of their complexes with the ions of the elements of atomic numbers 21-29, 42, 44 and 57-83; 2. for radiodiagnostxcs and radiotherapy in the form of their complexes with the radioisotopes of the elements of atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 10 64, 70 and 77.

The agents according to the invention fulfil the varied requirements for suitability as contrast agents for nuclear spin tomography. Accordingly, following oral or parenteral administration, they are excellently suitable 15 for improving the meaningfulness of the image obtained by means of the nuclear spin tomograph by increasing the signal intensity. Moreover, they exhibit the high degree of effectiveness which is necessary in order to subject the body to minimal amounts of foreign substances, and 0 the good tolerability necessary to maintain the noninvasive nature of the investigations.

Because of the good water-solubilitv and low osmolality of the agents according to the invention, it is possible to prepare highly concentrated solutions and thus keep the volume loading of the circulation within acceptable limits and compensate for dilution by the body fluid; that is to say, agents for NMR diagnostics must be 100to 1000-times more water-soluble than those for NMR spectroscopy. Furthermore, the agents according to th® invention exhibit not only a high stability in vifiCQ but also a surprisingly high stability jp vivo. so that the ions that are not bonded covalently in the complexes which ions are themselves toxic - are released or exchanged only extremely slowly during the time before which the novel contrast agents are completely excreted.

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

Especially low dosages (less than 1 mg/kg of body weight) of organ-specific NMR diagnostic agents can be used, for example, for detecting tumours and cardiac infarction.

The complex compounds according to the invention may also be used advantageously as susceptibility reagents and as shift reagents for in vivo NMR spectroscopy.

The agents according to the invention are also suitable 15 as radiodiagnostic agents on account of their advantageous radioactive properties and the good stability of the complex compounds they contain. Details of their use and administration are described, for example, in ’’Radiotracers for Medical Applications, CRC-Press, Boca 2o Raton, Florida.

A further imaging method using radioisotopes is positron emission tomography, which uses positron-emitting isotopes such as, for example, 43Sc, 44sc, 52Fe, 55Co and 68Ga. (Heiss, W.D., Phelps, M.E., Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York, 1983).

The compounds according to the invention can also be used in radioimmuno- or radio-therapy. This differs from the corresponding diagnostics only in the amount and nature 0 of the isotope used. The aim is to destroy tumour cells using high-energy short-wave radiation with a minimum range. Suitable β-emitting ions are, for example, 4®Sc, 47Sc, 48Sc, 72Ga and 73Ga. Suitable ©-emitting ions having short half-lives are, for example, 21~Bi, 2α2Βϊ, 213Bi and 214Bi, with 2123i being preferred. A suitable photon- and electron-emitting ion is 158Gd, which can be obtained from by neutron capture.

When the therapeutic agents according to the invention are used in vivo, they may be administered together with a suitable carrier such as, for example, serum or physiological saline solution and together with another protein such as, for example, Human Serum Albumin. The dose is dependent upon the nature of tha cell disorder, the metal ion used and the type of imaging method. 5 The therapeutic agents according to the invention are administered parenterally, preferably intravenously.

Details of the use of radiotherapeutics are discussed, for example, in R.W. Kozak et al. . TI3TEC, October 1986, 262.

The agents according to the invention are excellently suitable as X-ray contrast agents, and it is to be mentioned especially that in biochemical-pharmacological studies there were no signs of the anaphylactic-like reactions that are known to occur with iodine-containing contrast agents. The agents according to the invention are especially valuable on account of their advantageous absorption properties in regions of relatively high tube voltages for digital subtraction techniques.

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

Details of the use of X-ray contrast agents are discussed, for example, in Barke, Rontgenkontrastmittel, G. Thieme, Leipzig (1970) and P. Thurn, E. Biicheler, ’’Einfuhrung in die Rontgendiagnostik3’, G. Thieme, Stuttgart, New York (1977).

In summary, novel complexing agents, metal complexes and metal complex salts have successfully been synthesised, and they open up new possibilities in diagnostic and 10 therapeutic medicine. The development of new imaging processes in medicinal diagnostics in particular makes this development appear desirable.

The following Examples serve to illustrate the subject of the invention in greater detail.

EXAMPLE 1 a) 3,6,9-tris (p-tolylsulphonyl )-3,6,9,15-tetraazabicyclo[9.3.I]pentadeca-l(15),11,13-fcriene A solution of 35.2 g (200 mol) of 2,6-bis(chloromethyl )pyridine (dissolved in 700 ml of dimethylformamide) is added dropwise at 100’C, over a period of 3 hours, to 121.9 g (200 mol) of the N,N-disodium salt of Ν,Ν',Ν"tris(p-tolylsulphonyl )-diethylenetriamine in 1600 ml of dimethylformamide. The mixture is stirred overnight at 100’c. 2 litres of water are added dropwise to the hot solution, and the mixture is allowed to cool to 0C. The precipitate is filtered off with suction and washed with water. After drying in vacuo (60’C), the product is recrystallised from acetonitrile, yielding 92.3 g (69% of the theoretical yield) of the title compound in the form of a colourless powder.

Analysis: calc.; C 57.46 H 5.43 N 8.38 O 14.35 S 14.38 found: C 57.39 H 5.48 N 8.35 S 14.34 b) 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),11,13triene tetrahvdrosulphate 90.3 g (135 mmol) of the title compound of Example la are introduced into 270 ml of concentrated sulphuric acid, and the mixture is stirred for 48 hours at 100'C. The mixture is cooled to o’c, and 1.35 litres of absolute ether are added dropwise. The precipitate is filtered off with suction and precipitation is carried out by stirring in 800 ml of methanol. After filtration and concentration, the residue is dried Jjq vacuo at 50*C. Yield: 42.6 g (52.7% of the theoretical yield) of a solid that runs in air.

Analysis: calc.: 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,X5~tetraazabicyclo[9.3.1]pentadeca-l(15),11,13triene 40.0 g (66.8 mmol) of the title compound of Example Ic are dissolved in 100 ml of water, and the pH is adjusted to 11 with 32% sodium hydroxide solution. The mixture is extracted eight times with 150 ml of methylene chloride and dried over magnesium sulphate. Concentration by evaporation in vacuo yields 9.79 g (71% of the theoretical yield) of a yellowish powder.

Analysis: calc.: C 64.04 H 8.79 N 27.16 found: C 63.91 H 8.85 N 26,98 d) 3,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1jpentadeca-l(15),11,13-triene 33.1 g (55.1 mmol) of the title compound of Example Ic are adjusted to pH 8.5 in 170 ml of water with 6N potassium hydroxide solution. 20.84 g (220.5 mmol) of chloroacetic acid are added to that solution, the pH is adjusted to 9.5 with 6M potassium hydroxide solution, and the mixture is heated to 45’C. The mixture is stirred for 12 hours at that temperature and the pH value is kept at 9.5-10 by the addition of 6N potassium hydroxide solution. After cooling to room temperature, the pH is adjusted to 2 with concentrated hydrochloric acid and the mixture is concentrated to dryness by evaporation. The residue is extracted with 300 ml of ethanol/50 ml of acetone, the solid material is filtered off, and the filtrate is concentrated by evaporation in vacuo. The residue is dissolved in a small amount of water and passed over a cation exchange column (IR 120). After rinsing with water, the ligand is eluted with 0.5N aqueous ammonia solution. The fractions are concentrated by evaporation, taken up in a small amount of water and passed over an anion exchange column (IRA 67). First the column is washed with water, and then elution is carried out with 0.5M formic acid. Concentration is carried out by evaporation in vacuo and the residue is dissolved in a small amount of hot ethanol. The careful addition of acetone and cooling in an ice-bath cause the title compound to crystallise out.

Yield: 12.37 g (59% of the theoretical yield) of a very hygroscopic compound.

Analysis: calc.: C 53.67 H 6.36 H 14.73 O 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-tetraazabicyclo[9.3.1]pentadeca-l(15),11,13triene .0 g (13.14 nmol) of the title compound of Example Id are dissolved in 20 ml of deionised water and added to 2.38 g (6.57 nmol) of gadolinium oxide. The mixture is stirred for 3 hours at 90 *C. The solution is filtered and the filtrate is freeze-dried.

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

Analysis: calc.: 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 in plasma was measured (the relaxation times T1 were measured in a Hinispec p20 (Bruker) at 0.46 tesla (= 20 MHz) at 40*C): Τχ-relaxivity: 7.64 (L/mmol.sec) By way of comparison: dimeglumine salt of the gadolinium complex of diethylenetriaminepentaacetic acid (Gd-DTPA): Τχ-relaxivity: 4.95 (L/mmol.sec) Osmolality of a 0.5 molar solution at 37*C: 0.55 (Osml/kg water) 3v way of comparison: dimeglumine salt of Gd"DTPA; 1.1 (Osml/kg water).

In an analogous manner, using iron(III) oxide, Pe2O3, the iron(III) complex of 3,6,9-tris(carboxymethyl)-3,6,9,15tetraazabicyclo(9.3.1]pentadeca-l(15), 11,13-triene is obtained in the form of a brown powder.

Analysis (based on anhydrous substance): calc.: C 47.13 H 4.89 K 12.83 Fe 12.89 found: C 47.04 H 4.96 M 12.84 Fe 12.SI T^-relaxivity (L/mmol.sec), 40 *C, water, 20 MHz: 0.49. f) Dysprosium complex of 3,6,9-tris(carboxymethyl) 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13triene If dysprosium oxide is used instead of gadolinium oxide in Example le, then the title compound is obtained in virtually quantitative yield.

Analysis: calc.: C 37.82 H 3.92 N 10.38 O 17.78 Dv 30.10 found: C 37.87 H 3.98 N 10.24 Dy 30.02 g) Ytterbium complex of 3,6,9-tris(carboxymethyl)3,δ, 9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13triene If ytterbium oxide is used instead of gadolinium oxide in Example le, then the title compound is obtained in virtually quantitative yield.

Analysis: calc.: C 37.09 H 3.85 N 10.18 O 17.44 Yb 31.44 found: C 37.13 H 3.94 N 10.09 Yb 31.37 h) Meglumine salt of the manganese(II) complex of 3,6,9tris(carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(l5),11,13-triene 3.0 g (7.89 mmol) of the title compound of Example Id are dissolved in 20 ml of deionised water and added to 907 mg (7.89 mmol) of manganese(II) carbonate. The mixture is stirred for 2 hours at 80’C. The solution is filtered and the filtrate is adjusted to pH 7.2 with a 1 molar Nmethylglucamine solution. Then the product is freezedried.

Yield: 5.56 g (100% of the theoretical yield) of a slightly pink-looking amorphous powder which, according to the analysis, contains 12.2% water.

Analysis: calc.: C 45.85 H 5.25 N 11.14 O 28.00 Hn 8.74 found: C 45.98 H 5.21 N 11.08 Hn 8.68 EXAMPLE 2 a) 3,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadecane 6=0 g (15.77 nmol) of the title compound of Example Id are dissolved in 200 ml of 5% hydrochloric acid and hydrogenated in an autoclave over a rhodium catalyst (5% Rh/C) at 30 bar and 45C. After 4 hours, the catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo. The residue is purified over ion exchangers as described in Example Id. Crystallisation from methanol/acetone yields 4.75 g (78% of the theoretical yield) of an extremely hygroscopic compound. Analysis: calc.: C 52.83 H 7.83 N 14.50 O 24.84 found: C 52.94 H 7.89 N 14.37 b) Gadolinium complex of 3,6,9-tris(carboxyraethyl)3,6,9,15"tetraa2abicyclo[9.3.1]pentadecane 2.02 g (5.57 mmol) of gadolinium oxide are added to 4.3 g (11.13 mmol) of the title compound of Example 2a in 20 ml of deionised water, and the mixture is stirred for 3 hours at 90C. The solution is filtered and the filtrate is freeze-dried, yielding 6.5 g (100% of th® theoretical yield) of a white, flocculent powder which, according to the analysis, contains 10.3% water.

Analysis: calc.: C 37.76 H 5.03 N 10.36 O 17.76 Gd 29.08 found: C 37.63 K 5,12 N 10.33 Gd 28.97 EXAMPLE 3 a) 3,6,9--tris(acetyl)-3,6,9,15-tetraazabicyclo[9.3.1]™ penfcadeca-1(15),11,13-triene .8 g (76.6 irimol) of the title compound of Example Ic, 42.7 ral of triethylamine (306.4 mmol) and 50 mg of dimethylarainopyridine (DMAP) are dissolved in 300 ml of absolute methylene chloride. 28.9 ml (306.4 mmol) of acetic anhydride are added, and the raixture is stirred overnight at room temperature. The solvent is concentrated by evaporation in vacuo and the residue is taken up in 200 ml of 3% sodium carbonate solution. The mixture is extracted twice with 150 ml of methylene chloride. After drying the organic phase over magnesium sulphate, concentration is carried out by evaporation in vacuo.

The residue is recrystallised from ether/ethyl acetate, yielding 23.93 g (94% of the theoretical yield) of the title compound in the form of white flakes.

Analysis: calc.: C 61.42 H 7.28 N 16.86 O 14.44 found: C 61.48 H 7,37 N 16.80 b) 3,6,9-tris(acetyl)-3,6,9,I5-cetraa2abicyclo[9.3.1]pentadeca~l(15),11,13-triene-15-N-oxide 22.5 g (67.7 mmol) of the title compound of Example 3a are dissolved in 100 ml of glacial acetic acid. 7.7 ml of a 30% hydrogen peroxide solution are added, and the mixture is heated for 4 hours at 70’C. Then a further 3.9 ml of 30% hydrogen peroxide solution are added, and the mixture is stirred for a further hour at 7O'C, The mixture is concentrated in vacuo to a third, and saturated sodium carbonate solution is added carefully until the reaction is alkaline. The mixture is extracted twice with 250 ml of methylene chloride and then the organic phases are dried over magnesium sulphate. Concentration by evaporation in vacuo and crystallisation from ether/ethyl acetate yield 18.63 g (79% of the theoretical yield) of the title compound in the form of a crystalline powder.

Analysis: calc.: 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-tetraasabicyclo[9.3.1]pentadeca-l(15),11,13-triene-15-H~oxide 17 g (48.8 mmol) of the title compound of Example 3b are dissolved in 40 ml of 90% sulphuric acid and heated to 60 °C. 14 ml of concentrated nitric acid (d = 1.36) are added dropwise to the solution, and the mixture is stirred for 3 hours at 60°C. The mixture is poured onto 0 ice, and the precipitate is filtered and washed with a large amount of water. Drying in vacuo yields an orange powder, which is recrystallised from acetone.

Yield: 9.2 g (48% of the theoretical yield) of yellow rhombuses.

Analysis: calc.: C 51.90 H 5.89 H 17.80 O 24.40 found: C 52-01 H 5.76 N 17.64 d) 13,13’ -ethylenedioxv-bis [3,6,9-tris (acetyl )-3,6,9,15tetraazabicyclo[9.3.1 ]pentadeca-l(15), 11,l3-fcriene-1530 W-oxxde] A freshly prepared solution of ethylene glycol disodium in dimethyl formamide (prepared from 620 mg of ethanediol and 600 mg of sodium hydride [80% suspension in paraffin oil] in 15 ml of anhydrous dimethylformamide) is added dropwise over a period of 10 minutes to a solution, at 50'C, of 8 g (20.34 mmol) of the title compound of 5 Example 3c, and the mixture is stirred overnight at that temperature. 10 ml of water are added, and the mixture is concentrated by evaporation in vacuo. The residue is chromatographed on silica gel (eluant: methanol/32% aqueous ammonia solution = 10:1). Crystallisation from 10 ether/ethyl acetate yields 3.15 g (41% of the theoretical yield) of a yellowish crystalline powder.

Analysis: calc.: C 57.28 H 6.68 N 14.85 O 21.19 found: C 57.40 H 6.61 N 14.79 e) 13,13 e -ethylenedioxy-'bis[ 3,6,9-tris (acetyl )-3,6,9,15tetraazabicyclo[9.3.1]pentadeca-l(15),11,13-triene] g (3.97 mmol) of the title compound of Example 3d are dissolved in 100 ml of ethanol and added to 1 ml of concentrated hydrochloric acid, and the mixture is hydrogenated over Pd/C. The catalyst is filtered off, the filtrate is concentrated by evaporation in vacuo. and the residue is taken up in 50 ml of 3% sodium carbonate solution. The mixture is extracted twice with 100 ml of methylene chloride. After drying the organic phases over magnesium sulphate, the solvent is removed in vacuo and th© product is crystallised from ether/ethyl acetate. Yield: 2.87 g (87% of the theoretical yield) of white flakes.

Analysis: - 30 calc.: C 59.81 H 6.97 N 15.50 O 17.71 found: C 59.70 H 6.91 N 15.39 f) 13,13'"ethylenedioxy-bis[3,6,9 e 15-tetraasabicyclo[9.3.1]pentadeca-l(15),11, 13-triene] 2.5 g (3.46 mmol) of the title compound of Example 3e and 4.56 g (41.5 mmol) of potassium tert.-butoxide are 5 dissolved in 40 ml of dioxane, under nitrogen, and heated overnight under reflux. The mixture is concentrated. by evaporation in vacuo. and the residue is taken up in 50 ml of water and adjusted to pH 10 with 2N sodium hydroxide solution. After extraction six times with IQ 80 ml of methylene chloride each time, the mixture is dried over magnesium sulphate and the solvent is removed in vacuo.

Yield: 1.55 g (95% of the theoretical yield) of a pale yellow oil which crystallises when left to stand.

Analysis: calc.: C 61.25 H 8.14 N 23.81 O 6.80 found: C 61.17 H 8.20 N 23.93 g) 13,13'-ethylenedioxv-bis[3,6,9-tris(carboxymethyl)3,6,9,15-tetraazabicyclo[9.3.1]pentadeca~l(15),11,1320 triene] 1.4 g (2.97 mmol) of the title compound of Example 3f are dissolved in 20 ml of water and added to 2.25 g (23.8 mmol) of chloroacetic acid. The pH is adjusted to 9.5 with 6M potassium hydroxide solution. The mixture is stirred for 12 hours at 45C and the pH value is kept at 9.5-10 by the addition of 6H potassium hydroxide solution. The pH is adjusted to 2 with concentrated hydrochloric acid, and the mixture is purified over ion exchangers as described in Example Id. Crystallisation from ethanol/aceton® yields 1.3 g (57% of the theoretical yield) of the title compound in the form of a veryhygroscopic solid.

Analysis: calc.: C 52.80 H 6.16 N 13.69 O 27.35 found: C 52.67 H 6.07 M 13.75 h) Gadolinium complex of 13,13'-ethylenedioxy~bis[3,6,9tris (carboxymethyl )-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene] 1.2 g (1.47 mmol) of the title compound of Example 3g are dissolved in 8 ml of deionised water and added fo 533 mg (1.47 mmol) of gadolinium oxide. The mixture is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried.

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

Analysis: calc.: C 38.45 H 3.93 N 9.94 O 19.3" Gd 27.90 found: C 38.60 H 3.98 N 10.03 Gd 27.79 EXAMPLE 4 a) l3-ethynyl"3,6,9-tris(acetyl)-3,6,9,7.5-retraazabicyclo[9.3.1]pentadeca-l(15),11,ll-triene-lS-N-oxide g (25.42 mmol) of the title compound of Example 3c are dissolved, under nitrogen, in 200 ml of diaethoxyethane (DME). 1.22 g (25.42 mmol) of sodium acetylide (18% suspension in xvlene/light mineral oil) are added and the mixture is stirred overnight at room temperature- 10 ml of water are added, and the mixture is concentrated to dryness by evaporation. The residue is chromatographed on silica gel (eluant: methanol/acetone = 1:1). Crystallisation from ether/ethyl acetate yields 5.02 g (53% of the theoretical yield) of the title compound in the form of a pal® yellow powder.

Analysis: calc.: C 61.27 H 6.49 N 15.05 0 17.19 found: C 61.31 H 6.55 N 14.94 b) 13,13'-(1,3-butadiyne-l,4-diyl)-bis ([3,6,9-tris~ (acetyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca~ 1(15),ll,13-triene]~15~N-oxide) 4.75 g (12.75 mmol) of the title compound of Example 4a are dissolved in 200 ml of pyridine, and 2.52 g (25.5 mmol) of copper(I) chloride are added. The solution is saturated with, oxygen and then stirred for two days at room temperature. During that time it must be ensured that an oxygen atmosphere is maintained at all times. After concentration of the solution in vacuo. the residue is chromatographed on silica gel (eluant: methanol/acetone = 1:2). Crystallisation from ether/ethyl acetate yields 2.7 g (57% of the theoretical yield) of a slightly yellowish powder.

Analysis: calc.: C 61.27 H 6.49 M 15.05 0 17.19 found: C 61.31 H 6.55 M 14.94 c) 13,13'"(1,3-butadiyne-l,4-diyl)-bis[3,6,9-tris(acetyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca1(15),11,13-triene] 2.5 g (3.37 ifimol) of the title compound of Example 4b are dissolved in 50 ml of glacial acetic acid and heated to SO’C. 1.88 g (33.65 mmol) of iron powder are added and the mixture is stirred for 2 hours at 60*C- The solid material is filtered off and the filtrate is concentrated to dryness by evaporation. The residue is taken up in 100 ml of 3% sodium carbonate solution and is extracted three times with 100 ml of chloroform. After drying over magnesium sulphate, the solvent is removed ia vacuo and crystallisation is carried out from ether/acetone.

Yield: 2.08 g (87% of the theoretical yield) of a colourless powder.

Analysis: calc.: C 64.21 H 6.52 N 15.77 O 13.51 found: C 64.31 H 6.60 Η 15.68 d) 13,13^-(1,3-butadiyne-l,4-diyl)-bis[3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),11,13-triene] 1.9 g (2.67 mmol) of the title compound of Example 4c are dissolved, under nitrogen, in 20 ml of dioxane. 2.4 g (21.38 mmol) cf potassium tert.-butoxide are added, and the mixture is boiled under reflux overnight. The solvent is removed in vacuo and the residue is taken up in 20 ml of water. The pH is adjusted to 10 with 2N sodium hydroxide solution and the mixture is extracted six times with 60 ml of methylene chloride. After drying the organic phases over magnesium sulphate, the product is concentrated by evaporation in vacuo.

Yield: 1.09 g (39% of the theoretical yield) of a pale yellow oil.

Analysis: calc.: C 63.09 H 7.47 N 24.44 found: C 63.13 H 7.54 N 24.51 e) 13,13'-(1,3-butadiyne-l,4-diyl)-bis[3,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene] 1.0 g (2.18 mmol) of the title compound of Example 4d is dissolved in 15 ml of water and added to 1.65 g (17.44 mmol) of chloroacetic acid. The pH is adjusted to 9.5 with 6H potassium hydroxide solution, and the mixture is stirred for 12 hours at 45 C. During that time, the pH value is kept at 9.5-10 by the addition of 6N potassium hydroxide solution. After acidification with concentrated hydrochloric acid, purification is carried out over ion exchangers as described in Id. Crystallisation from methanol/acetone yields 1.07 g (61% of the theoretical yield) of a very hygroscopic solid.

Analysis: calc.: C 56.57 H 5./5 N 13.89 O 23.79 found: C 56.64 H 5.81 N 13.79 f) Gadolinium complex of 13,13'-(1,3-butadiyne-l,4-diyl )10 bis [3,6,9-tris (carboxymethyl )-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),11,13-triene] 900 mg (1.116 mmol) of the title compound of Example 4e are dissolved in 8 ml of water and added to 404 mg (1.116 mmol) of gadolinium oxide. After stirring for 3 hours at 90"C, the solution is filtered and the filtrate is freeze-dried.

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

Analysis: calc.: C 40.92 H 3.62 N 10.05 O 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-tetraazabi25 cyclo[9.3.1]pentadeca-l(15),11,13-triene-15~N-oxide 7.3 g (18.56 mmol) of the title compound of Example 3c are heated in 50 ml of acetyl chloride for 4 hours at 50*c. The mixture is concentrated in vacuo and the residue is taken up in 200 ml of 3% sodium carbonate solution. The mixture is extracted three times with 100 ml of chloroform and is dried over magnesium sulphate. After removal of the solvent vacuo. the product is recrystallised from ether/ethyl acetate.

Yield: 6.18 g (87% of the theoretical yield) of a colourless crystalline powder.

Analysis; calc.: 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-tetraazabicyclo[9.3.1lpentadeca-1(15),11,13-triene 6.0 g (15.67 mmol) of the title compound of Example 5a are dissolved in 300 ral of ethanol. 1 ml of concentrated hydrochloric acid is added, and the mixture is hydrogenated over Pd/C. when the absorption of hydrogen has ceased, the catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo. The residue is taken up in 100 ral of 3% sodium carbonate solution and is extracted twice with 100 ml of chloroform. The organic phases are dried over magnesium sulphate and concentrated by evaporation in vacuo. Crystallisation of the residue 2° from ether/ethyl acetate yields 5.34 g (93% of the theoretical yield) of the title compound in the form of a colourless powder.

Analysis: calc.: 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-tetraazabicyclo[9.3.1]pentadeca1(15),11,13-triene .1 g (13.9 mmol) of the title compound of Example 5b are dissolved, under nitrogen, in 50 ml of dioxane. 6.24 g (55.6 mmol) of potassium tert.-butoxide are added, and the mixture is boiled under reflux overnight. Working up is carried out as described in Example 4d.

Yield: 3.01 g (90% of the theoretical yield) of a slightly yellowish oil, which crystallises after a short time.

Analysis: calc.: C 54,88 H 7.12 found: C 54.93 H 7.0S N 23.28 Cl 14.73 M 23.41 Cl 14.81 d) 13-chloro-3,6,9-tris (carboxymethyl )-3,6,9,15-tetraazabicyclot 9.3.1]pentadeca-l(15),11,13~triene 2.38 g (11.65 mmol) of the title compound of Example 5c are dissolved in 30 ml of water and added to 4.4 g (46.6 mmol) of chloroacetic acid. The pH is adjusted to 9.5 with 6N potassium hydroxide solution. The mixture is stirred for 12 hours at 45 °C and the pH value is kept at 9.5-10 by the addition of 6M potassium hydroxide solution. Working up as described in Example Id and crystallisation from methanol/acetone yield 3.23 g (67% of the theoretical yield) of the title compound in the form of a solid that deliquesces in air.

Analysis: calc.: 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-tetraazabicvclo[9.3.1]pentadecalf 15 ) , 11,13-triene 3.23 g (7.78 mmol) of the title compound of Example 5d are dissolved in 20 ml of deionised water and added to 1.41 g (3.89 mmol) of gadolinium oxide. The mixture is stirred for 3 hours at 90'C. The solution is filtered and the filtrate is freeze-dried.

Yield: 4.9 g (100% of the theoretical yield) of a white amorphous powder which, according to the analysis, contains 11.9% water.

Analysis: calc.: C 35.88 H 3.54 N 9.85 O 16, ,87 Cl 6.23 Gd 27.63 found: C 35.94 H 3.57 N 10.01 Cl 6.17 Gd 27.56 T^-relaxivity (L/mmol. ,sec), 40* 'c, water, , 20 MHz: : 5.44.

EXAMPLE δ a) 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),11,13triene-15-N-oxide 4.5 g (12.9 mmol) of the title compound of Example 3b are dissolved, under nitrogen, in 40 ml of dioxane. 5.8 g (51.7 mmol) of potassium tert.-butoxide are added, and the mixture is boiled under reflux overnight. Working up as described in Example 3f yields 2.61 g (91% of the theoretical yield) of a pale yellow oil, which crystallises when left to stand.

Analysis: calc.: C 59,43 H 8.16 M 25.20 0 7.20 found: C 59.37 H 8.21 N 25.13 b) 3,6,9-tris(carboxvmethyl)-3,6,9,15-tetraazabicvclo[9.3.1]pentadeca~l(15),11,13-triene-15-N-oxide 2.4 g (10.77 mmol) of the title compound of Example 6a are dissolved in 30 ml of water and added to 4.1 g (43.4 mmol) of chloroacetic acid. The pH is adjusted to 9.5 with 6N potassium hydroxide solution. The mixture is stirred for 12 hours at 45'C and the pH value is kept at 9.5-10 with the addition of 6N potassium hydroxide solution- After working up as described in Example Id, crystallisation from ethanol/acetone yields 2.7 g (63% of the theoretical yield) of a very hygroscopic powder. Analysis: calc.: C 51.51 H 6.10 N 14.14 O 28.26 found: C 51.S3 H 6.01 N 14.08 c) Gadolinium complex of 3,6,9-tris(carboxyaethyl)3,6,9,15-tetraazabicyclo[9.3.1]pentadecs-l(15) ,11,13triene-15-N-oxide 2.1 g (5.3 mmol) of the title compound of Example 5b are dissolved in 15 ml of deionised water and added to 935 mg (2.65 mmol) of gadolinium oxide. Th® mixture is stirred for 3 hours at 90’C. The solution is filtered and the filtrate is freeze-dried.

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

Analysis: calc.: C 37.08 found: C 37.18 H 3.84 H 3.79 N 10.18 0 20.34 Gd 28.56 N 10.21 Gd. 28.48 EXAMPLE 7 a) 3,6,9~tris(p-tolylsulphonyl)-3,6,9-triaza-14-oxabicyclo[9.2.l]tetradeca-1(13),11-diene A solution of 33 g (200 mmol) of 2,5-bis(chloromethyl) furan in 700 ral of dimethylformamide is added dropwise at 100eC, over a period of 3 hours, to 121.9 g (200 mmol) of the N,N-disodium salt of N,N' ,N"-tris(p-tolylsulphonyl)" diethvlenetriaraine in 1600 ral of diraethylforaaraide. The mixture is stirred overnight at 100c. 2 litres of water are added dropwise to the hot solution. The mixture is cooled to 0C« The precipitate is washed with a large amount of water and is dried in vacuo (60’C). Crystallisation from acetonitrile yields 88.14 g (67% of the theoretical yield) of a white powder.

Analysis: calc.: C 56.60 H 5.36 N.6.39 O 17.03 S 14.62 found: C 56-52 H 5.42 M 6.30 S 14.60 b) 3,6,9-triaza-14-oxabicyclo[ 9.2.1]tetradeca-1 (13), 11diene g (45.61 mmol) of the title compound of Example 7a are suspended in 500 ml of liquid ammonia at -40'c. Then 10.49 g (456.1 mmol) of sodium are added over a period of 30 minutes, and the mixture is stirred for 3 hours at -40’C. The excess sodium is destroyed by the careful addition of ethanol (decolouration), and ammonia Is allowed to evaporate off. The residue is taken up in 100 ml of water and adjusted to pH 11 with 6N sodium hydroxide solution. Then the mixture is extracted six times with 150 ml of methylene chloride, and the organic phase is dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel (eluant: acetonitrile/water/32% ammonia solution = 10:3:1).

Yield: 3.95 g (45% of the theoretical yield) of a pale yellow oil.

Analysis: calc.: C 61.51 H 8.78 N 21.52 O 8.19 found: C 61.43 H 8.85 N 21.47 c) 3,6,9-tris(ethoxycarbonylmethyl)-3,6,9-triaza-14oxabicyclo [9.2.1]tatradeca-1(13),11-diene ml (62.5 mmol) of bromoacetic acid ethyl ester are slowly added dropwise at 50 "C, over a period of 10 minutes, to a mixture of 3.7 g (18.95 mmol) of the title compound of Example 7b and 6.03 g (56.85 mmol) of anhydrous sodium carbonate in 150 ml of dimethylformamide. The mixture is stirred for 4 hours at 50’C. The solvent is removed in vacuo and the residue is precipitated by stirring In 200 ml of methylene chloride. The solid material is filtered off and the filtrate is concentrated by evaporation. The oil that remains is chromatographed on silica gel (eluant: methylene chloride/ethanol = 12:1)Yield: 6.1 g (71% of the theoretical yield) of a yellowish oil, which solidifies slowly.

Analysis: calc.: C 58.26 H 7.78 N 9.27 O 24.69 found: C 58.17 H 7.88 H 9.19 d) Gadolinium complex of 3,6,9-tris(carboxymethyl)3,6,9-triaza-14-oxeibicyclo[9.2.1 ]tetradeca-l( 13), 1110 diene .0 g (11.02 mmol) of the title compound of Example 7c are dissolved in 80 al of ethanol and slowly added dropwise at 60 C to 36 ml of IN sodium hydroxide solution. The mixture is heated under reflux for 30 minutes.

The mixture is concentrated fo dryness by evaporation, the residue is taken up in 20 ml of water, and the pH is carefully adjusted to 6.5 with 2N hydrochloric acid. After the addition of 2.0 g (5.57 mmol) of gadolinium oxide, the mixture is stirred for 3 hours at 90*C. The solution is filtered and the filtrate is passed first over a short cation exchange column (IR-120) and then over a short anion exchange column (IRA-67). The eluate is freeze-dried.

Yield; 4.9 g (78% of the theoretical yield) of an amorphous powder which, according to the analysis, contains 9.7% wafer.

Analysis: C 36.70 H 3.85 N 8.03 0 21.39 Gd 30.03 C 36.51 H 3.81 K 8.11 Gd 29.91 EXAMPLE S Gadolinium complex of 3,6,9-tris(carboxymethyl)3,6,9,14~tetraazabicyclo[9.2.1]tetradeca-l (13), li-diene .0 g (22.04 mmol) of the title compound of Example 7c are dissolved in 150 ml of ethanol and added dropwise at 60’C to 80 ml of IN sodium hydroxide solution. The mixture is boiled under reflux for one hour and is then concentrated to dryness toy evaporation. The residue is transferred to a shaking autoclave, and 3.54 g (66.12 mmol) of ammonium chloride are added. After the addition of vanadium oxide catalyst (US Patent 2 478 456, Chem. Atostr. 44.a 665 (1950)), 100 ml of ammonia are condensed in. The mixture is heated for 12 hours at 200’C. After removal of the ammonia by evaporation, the residue is chromatographed on silica gel (eluant: dioxane/water/32% aqueous ammonia solution = 6:2:1). Concentration by evaporation yields approximately 5.19 g (56% of the theoretical yield) of the extremely hygroscopic ammonium salt, which is immediately reacted further. It is dissolved in 25 ml of deionised water and the pH is adjusted to 6.5 with 2N hydrochloric acid. 2.24 g (6.17 mmol) of gadolinium oxide are added, and the mixture is stirred for 3 hours at 90"c, under nitrogen. 1 g of activated carbon is added, and the mixture is stirred for a further hour at 90C. The solution is filtered and the filtrate is passed first over a short cation exchange column (IH-120) and then over a short anion exchange column (ISA-67). The eluate is freeze-dried.

Yield: 6.0 g (47% of the theoretical yield, based on the title compound of Example 7c) of an amorphous powder which, according to the analysis, contains 11.1% water.

Analysis: calc.: C 36.84 H 3.87 Μ 10.74 O 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-tolylsulphonyl)-3,6,9-triazabicyclo[9.3.13pantadeca-l(15),IX,13-triene 182.85 g (300 mmol) of the N,N-disodium salt of N,Ν',NMtris(p-tolylsulphonyl)diethylenetriaaine are dissolved in 2.4 litres of dimethylformamide and heated to 100*C. A solution of 88.2 g (300 mmol) of 2,6-bis(bromomethyl)phenol methyl ether in one litre of dimethylformamide is added dropwise over a period of 3 hours. The mixture is stirred overnight at 100°C. 3 litres of water are added dropwise to the hot solution, which is cooled to 0C.

The precipitate is washed with a large amount of water and dried in vacuo (60*C). Crystallisation from acetonitrile yields 119.3 g (57% of the theoretical yield) of the title compound in the form of a slightly creamcoloured powder.

Analysis: calc.: C 58.51 H 5.63 N 6.02 0 16.05 S 13.78 found: C 58.41 H 5.68 N 6.13 S 13.70 b) 15-hydroxy~3,6,9~triazabicyclo[9.3.I]pentadeca1(15),11,13-triene 21.75 g (573.2 mmol) of lithium aluminium hydride are added carefully to 100 g (143.3 mmol) of the title compound of Example 9a in 2 litres of dibutyl ether, and the mixture is heated under reflux overnight. The mixture is cooled in an ice-bath and excess lithiuaa aluminium hydride is destroyed with ethanol and then with water. The mixture is concentrated to dryness by evaporation, and the residue is taken up in one litre of 2M sodium hydroxide solution and extracted ten times with 200 ml of chloroform. After drying over magnesium sulphate, concentration is carried out in vacuo and the residue is chromatographed over silica gel (eluant: methanol/32% aqueous ammonia solution = 10:1).

Yield: 8.56 g (27% of the theoretical yield) of a yellowish oil.

Analysis: calc.: C 65.13 H 8.65 N 18.99 O 7.23 found: C 65.18 H 8.60 N 19.10 c) 15-hydroxv-3,6,9-tris (tert.-butoxycarbonylmethyl)3,6,9-triazabicyclo[9.3.1]pentadeca-X(15) , 11,13-triene 8.3 g (37.50 mmol) of the title compound of Example 9b are dissolved in 250 ml of dimethylformamide and added to 15.55 g (112.5 mmol) of anhydrous potassium carbonate. 16.3 ml (112.5 mmol) of bromoacetic acid tert.-butyl ester are added dropwise over a period of 30 minutes, and the mixture is stirred overnight at room temperature.

The solvent is evaporated off to dryness, the residue is taken up in 300 ml of water, and extraction is carried out three times with 150 ml of methylene chloride. The organic phases are dried over magnesium sulphate and concentrated by evaporation in vacuo. The oil that remains is chromatographed on silica gel (eluant: methylene chloride/methanol ~ 15:1).

Yield: 13.32 g (63% of the theoretical yield) of the title compound in the form of a colourless oil.

Analysis: calc.: C 63.91 H 8.76 N 7.45 0 19.87 found: C 63.83 H 8.85 N 7.49 d) l5-hydroxv-3,6,9-tris (carboxymethyl)-3, 6,9-triasabicyclo[9.3.1]pentadeca-1(15),11, 13-triene 13.0 g (23.05 mmol) of the title compound of Example 9c are dissolved in 150 ml of trifluoroacetic acid and stirred overnight at room temperature. The mixture is concentrated in vacuo. The residue is taken up in a small amount of water and purified over ion exchangers as described in Example Id. Crystallisation from methanol/acetone yields 6.5 g (71% of the theoretical yield) of the title compound in the form of a powder that deliquesces in air.

Analysis: calc.: 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(carboxy» methyl)-3,6,9-triazabicyclo[9.3.1]pentadeca1(15),11,13-triene 4.0 g (10.1 mmol) of the title compound of Example 9d are dissolved in 25 ml of deionised water and added to 1.84 g (5.05 mmol) of gadolinium oxide. The mixture is stirred for 3 hours at 90 *C, 1 g of activated carbon is added, and the mixture is stirred for a further hour at that temperature. The solution is filtered and the filtrate is freeze-dried, yielding 6.04 g (96% of the theoretical yield) of an amorphous powder which, according to the analysis, contains 13.5% water.

Analysis: calc-: C 39.33 K 4.04 N 7.65 0 20.38 Gd 2^,61 found: C 39.41 H 4.10 M 7.58 Gd 28.51 EXAMPLE 10 a) 6-benzyl-3,S-bis(p-tolylsulphony1)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15), 11,13-triene A solution of 35»2 g (200 mmol) of 2,6-bis(chloromethyl )pyridine (dissolved in 700 ml of dimethylformamide) is added dropwise at 100°C, over a period of 3 hours, to 109.12 g (200 mmol) of the N,N"-disodium salt of N, Nbis (p-tolvlsulphonyl) -N ' -benzvldiethylenetriamine in 1500 ml of dimethylformamide. The mixture is stirred overnight at 100’c, 2 litres of water are added dropwise to the hot solution, and the mixture is cooled to O’C. The precipitate is washed several times with water and is dried in vacuo (60°C). Crystallisation from acetonitrile/ether yields 78.6 g (65% of the theoretical yield) of a cream-coloured powder.

Analysis: calc.: C 63.55 H 6.00 N 9.26 0 10.58 S 10.60 found: C 63.48 H 5.94 N 9.18 S 10.63 b) 6~bensyl"3,6,9,l5-tetraazabicvclo[9.3.1Ipentadeca1(15),11,13-triene 9.41 g (248 mmol) of lithium aluminium hydride are added carefully to 75 g (124 mmol) of the title compound of Example 10a in 1.5 litres of dibutvl ether, and the mixture is heated under reflux overnight. After cooling in an ice-bath, the excess lithium aluminium hydride is destroyed with ethanol and water. The mixture is concentrated to dryness by evaporation and the residue is taken up in 500 ml of water and adjusted to pH 11 with 6N potassium hydroxide solution. Extraction Is carried out six times with 100 ml of chloroform, followed by drying over magnesium sulphate and concentration jja vacuo Chromatography on silica gel (eluant: ethanol/32% aqueous ammonia solution - 3.2:1) yields 22.4 g (61% of the theoretical yield) of a yellowish oil, which solidifies to a transparent solid.

Analysis: calc.: 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 (ethoxycarbonyImethyl )-3,6,9,15tetraazabicyclo [9.3.1]pentadeca-l(15),11,13-triene g (33.74 mmol) of the title compound of Example 10b are dissolved in 300 ml of dimethylformamide. 7.13 g (67.48 mmol) of anhydrous sodium carbonate are added, and the mixture is heated to 50’C. Then 8.3 ml (74.2 mmol) of bromoacetic acid ethyl ester are added dropwise over a period of 15 minutes, and the mixture is stirred overnight at 50’c. The solvent is removed by evaporation in vacuo. and the residue is precipitated twice by stirring with 350 ml of methylene chloride, is filtered and is concentrated. The oil that remains is chromatographed on silica gel (eluant: methylene chloride/ethanol = :1).

Yield: 13.3.2 g (83% of the theoretical yield) of the title compound in the form of a colourless oil.

Analysis: calc.: C 66.64 H 7.74 M 11.96 O 13.66 found: C 66.51 H 7.81 N 11.88 d) 3,9-bis(carboxvmethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),11,13-triene g (25.6 mmol) of the title compound of Example 10c are dissolved in 100 ml of ethanol and heated to 60 C. 32 ml of 21« sodium hydroxide solution are added dropwise to that solution, and the mixture is boiled under reflux for one hour. Th© mixture is concentrated to dryness by evaporation and the residue is dissolved in 200 ml of 5% acetic acid. Hydrogenation is carried out over Pd/C.

When the absorption of hydrogen has ceased, the catalyst is filtered off, the filtrate is concentrated in vacuo, and the residue is purified over ion exchangers as described in Example Id. Crystallisation from ethanol/acetone yields 6.52 g (79% of the theoretical yield) of a very hygroscopic solid.

Analysis: calc.: C 55.88 H 6.88 N 17.38 O 19.85 found: C 55.79 H 6.94 N 17.27 e) Manganese(II) complex of 3,9-bis(carboxymethyl)3,6,9,15-tetraazabicycIof 9.3.l'pentadeca-l(15),11,13triene g (12.4 mmol) of the title compound of Example lOd are dissolved in 20 ml of deionised water and added to 1.43 g (12.4 mmol) of manganese(II) carbonate. The mixture is heated at 80°C for 2 hours. The solution is passed first over a short cation exchange column. (IR-120) and then over a short anion exchange column (IRA-67). The eluate is boiled under reflux for one hour with 1 g of activated carbon and is filtered. The filtrate is freeze-dried, yielding 4.4 g (87% of the theoretical yield) of a slightly pink-tinged amorphous powder.

Analysis: calc.: C 48.00 H 5.37 N 14.93 O 17.95 Mn 14.64 found: C 47.93 H 5.41 N 14.87 Mn 14.58 EXAMPLE 11 a) 3,6-bis(p-tolylsulphonyl)-3,6,12-triazabicyclo[6.3.1]dodeca-l(12),8,10-triene A solution of 35.2 g (0.2 mol) of 2,6-bis (chloromethyl)50 pyridine (dissolved in 700 ml of dimethylformamide) is added dropwise at 100"C, over a period of 3 hours, to 82.48 g (0.2 mol) of the disodium salt of M,M'"bis(ptolylsulphonyl)ethylenediamine in 1600 ml of dimethylformamide. The mixture is stirred overnight at 110’C. litres of water are added dropwise to the hot solution, and the precipitate is filtered off with suction and washed with a large amount of water. After drying ija vacuo (60'C), the product is recrystallised from acetonitrile.

Yield: 67.9 g (72% of the theoretical yield) of a creamcoloured powder.

Analysis: calc.: C 58.58 H 5.34 N 8.91 O 13.57 S 13.60 found: C 58.41 H 5.37 H 8.85 S 13.53 to) 3,6,12-triazabicyclo[6.3.1]dodeca~l(12),8,10-triene trihydrosulphate 67.0 g (142 mmol) of the title compound of Example Ila are introduced into 200 ral of concentrated sulphuric acid and stirred for 48 hours at 100C. The mixture is cooled to 0eC and one litre of absolute ether is added dropwise. The precipitate is filtered off with suction and precipitated by stirring in 600 ml of methanol. The mixture is filtered and then concentrated to dryness by evaporation. Drying ia vacuo (60eC) yields 44.17 g (68% of the theoretical yield) of the title compound in the form of a crystalline solid.

Analysis: calc.: C 23.63 H 4.19 N 9.19 O 41.97 S 21.03 found: C 23.57 H 4.24 N 9.11 S 20.96 c) 3,6,12-triazabicyclo[6.3.1]dodeca~l(12),8,10-triene 42.0 g (91.8 mmol) of the title compound of Example 11b are dissolved in 100 ml of water and adjusted to pH 11 with 32% sodium hydroxide solution. Extraction is carried out six times with 200 ml of methylene chloride and the combined phases are dried over magnesium sulphate. Concentration by evaporation in vacuo yields 11.24 g (75% of the theoretical yield) of a slightly yellow oil.

Analysis: calc.: C 66.23 K 8.03 N 25.74 found: C 66.17 H 8.09 N 25.67 d) 3,6-bis (carboxymethvl )-3,6,12-triazabicyclo [6.3.1]dodeca-1(12),8,10-triene g (61.27 mmol) of the title compound of Example 11c are dissolved in 100 ml of water and added to 17.37 g (183.8 mmol) of chloroacetic acid. The pH is adjusted to 9.5 by the addition of 6M potassium hydroxide solution and the mixture is heated to 45’C. The mixture is stirred for 12 hours at that temperature, the pH value being kept at 9.5-10 by the addition of 6N potassium hydroxide solution. The mixture is cooled and purified over ion exchangers as described in Example Id. Crystallisation from ethanol/acetone yields 11.47 g (67% of the theoretical yield) of the title compound in the form of a crystalline solid.

Analysis: calc.: C 55.90 H 6.14 M 15.05 O 22.92 found: C 55.81 H 6.19 N 14.94 e) Manganese complex of 3,6-bis(carboxymethyl)-3,6,12triazabicyclo[6.3.1 ]dodeca-l(12),8,10-triene .0 g (35.8 mmol) of the title compound of Example lid are dissolved in 40 ml of deionised water and added to 4.12 g (35.8 mmol) of manganese(II) carbonate. The mixture is stirred for 2 hours at 80G. The solution is passed over a short anion and cation exchange column and the eluate is stirred with 1 g of activated carbon for one hour at 80c. The mixture is filtered and the filtrate is freeze-dried.

Yield: 12.7 g (96% of the theoretical yield) of the title compound in the form of an amorphous powder which, according to the analysis, contains 11.3% water.

Analysis: calc.: C 47.00 H 4.55 N 12.65 O 19.26 Mn 16.54 found: C 46.95 H 4.61 N 12.58 Mn 16.48 EXAMPLE 12 Preparation of a solution of the gadolinium complex of 3,6,9-tris (carboxymethyl )-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene 534.63 g (1 mol) of the compound described in Example le were dissolved in 1200 ml of water pro injections (p.i.). After the addition of 24.62 g (50 mmol) of the monohydrate of the calcium trisodium salt of DTPA, CaNa3DTPA, the solution is made up to 2000 ml with water p.i.. The solution is then ultrafiltered, transferred into ampoules and heat-sterilised, and is ready for use for parenteral administration.

Preparation of a solution of the meglumine salt of the manganese(II) complex of 3,6,9-tris(carboxymathyl)3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1 (15) ,11,13triene 34.92 g (50 mmol) of the compound described in Example Ih (water content 12.29%) are dissolved in 65 ml of water (p.i.). After the addition of 492 sag (1 mmol) of the monohydrate of the calcium trisodium salt of DTPA, CaNagDTPA, the solution is made up to 100 ml with water p.i.. The solution is then ultrafiltered, trans5 ferred into ampoules and heat-sterilised, and is ready for use for parenteral administration.

EXAMPLE 14 Composition of a powder for the preparation of a suspension for oral administration: 4.000 g of 3.895 g of 0.100 g of 0.005 s of 8.000 g EXAMPLE 15 the gadolinium complex described mannitol polyoxvethylene-polyoxypropylene flavourings in Example le polymer Preparation of a solution of the indium-111 complex of 3,6,9-tris (carboxymethyl)-3,6,9,15-tetraazabicvclo[9.3.1]pentadecane A solution of 5 ml of indium-111 chloride in 1 ml of N hydrochloric acid is added to a solution of 100 pg of the compound described in Example 2a in 5 ml of a mixture of a 150 mmolar sodium chloride solution and a 150 mmolar sodium acetate solution (pH 5.8). The pH is adjusted to 7.2 by the addition of 0.1N sodium hydroxide solution, and the sterile-filtered solution is introduced into multi-vials and lyophilised. The residue is taken up in physiological saline solution and is then a preparation suitable for radiodiagnostics.

A preparation suitable for radiotherapy is obtained in an analogous manner using yttrium-90 chloride.

EXAMPLE 16 a) 3,6,9—tris(p-tolylsulphonvl)-14-oxa-3,6,9-triazabicyclo[9.2.1]tetradecane 39.01 g (64 mmol) of the N»N"-disodium salt of N,N',Nmtris(p"tolylsulphonyl)diethylenetrfamine dissolved in 210 ml of dimethylformamide are added dropwise at 100C, over a period of 2 hours, to a solution of 28.19 g (64 mmol) of 2,5-bis(p-tosyloxymethyl)tetrahydrofuran in 500 ml of dimethylformamide, and the mixture is stirred for 5 hours at 120°C. 700 ml of water are added dropwise to the hot solution, which is then cooled to O'C. The precipitate is filtered off with suction, washed with water and dried in vacuo at 50’. Recrystallisation from 15 acetone yields 33.5 g of the title compound in the form of a white powder, melting point 175-T78"C.

Analysis: calc.: C 56.26 H 5.94 N 6.35 S 14.53 found: C 56.01 H 5.99 fi 6.28 S 14.29 20 b) 14-oxa-3,6,9"triazabicyclo[9.2.1Jtetradecane g (45.3 mmol) of the title compound of Example 16a are introduced into 90 ml of concentrated sulphuric acid and stirred for 24 hours at 90 C. The mixture is then cooled to 0’C, and 350 ml of dry ether are added drop25 wise. The precipitate that forms is filtered off with suction, and dissolved in 50 ml of 40% sodium hydroxide solution, and the solution is extracted ten times with 50 ml of dichloromethane each time. The organic phase is dried over magnesium sulphate and concentrated by evaporation in vacuo., yielding 6.23 g (69% of the theoretical yield) of th® title compound in the form of a white powder.

Analysis: calc.: C 60.27 H 10.62 N 21.08 found: C 60.03 H 10.75 N 20.95 c) 3,6,S-tris(carboxymethyl)-14-oxa-3,6,9-triazabicyclo[9.2.1]tetradecane g (30.1 mmol) of the title compound of Example 16b are dissolved in 35 ml of water; 11.38 g (120.4 mmol) of chloroacetic acid are added, and the solution is adjusted to pH 9.5 with 6N potassium hydroxide solution. The mixture is heated for 12 hours at 45°C and the pH value is kept at 9.5-10 during that time by the addition of further potassium hydroxide solution. Then the mixture is cooled to room temperature, concentrated hydrochloric acid is added slowly until the pH reaches 2, and the mixture is concentrated by evaporation in vacuo. The residue is dissolved in 100 ral of water and the solution is passed over a cation exchange column (IR 120). The column is first washed with a large amount of water.

Then the desired substance is eluted with 0.5N ammonia solution, the solution is concentrated by evaporation, the residue is dissolved in 100 ml of water, and the solution is passed over an anion exchange column (IRA 67). First the column is washed with water, and then elution is carried out with 0.5N formic acid. The acid fractions are concentrated by evaporation and the residue is dissolved in methanol. After the addition of acetone, the title compound crystallises out (5.74 g, 51% of the theoretical yield).

Analysis: calc.; C 51.47 H 7.29 N 11.25 found: C 51.60 H 7.21 N 11.38· d) Gadolinium complex cf 3,6,9-tris(carboxymethyl)-14oxa-3,6,9~tria2abicyclo[9.2.1]tetradecane 3.73 g (10 mmol) of the title compound of Example 16c are dissolved in 15 rati cf water and stirred for 3 hours with 1.81 g (5 mmol) of gadolinium oxide at 80C. The resulting solution is filtered and is precipitated by stirring with, in succession, 0.5 g of cation exchanger (IR 120) and 0-5 g of anion exchanger (IRA 67); the solution is filtered again and is subjected to freezedrying, yielding 5.07 g (91% of the theoretical yield) of the title compound in the form of a white amorphous powder having a water content of 5.4%.

Analysis: calc.: C 36.42 H 4.59 N 7.96 Gd 29.80 found: C 36.30 H 4.61 S 7.82 Gd 29.59 (water content taken into account) EXAMPLE 17 a) 3,6,9-tris(p-tolylsulphonyl)-14-thia-3,6,9-triazabicyclo[9.2.1]tetradeca-l(13),Xl-diene 60.97 g (100 mmol) of the N,Ν'»-disodium salt of Ν,Ν',Η’’tris(p-tolylsulphonyl)diethylenetriamine are dissolved in 800 ml of dimethylfcrmanide, and 19.9 g (110 mmol) of 2, S-hischloromethyXthiophene dissolved in 3 30 ml of dimethylformamide ©re added dropwise at 50 ’C over a period of 90 minutes. The mixture is stirred for a further 90 minutes at 50C, one litre of water is then added dropwise, and the precipitate that forms is filtered off with suction and washed with water; the residue is dried at 50"c in a vacuum drying cabinet and is recrystallised from dioxane. 47.1 g (70% of the theoretical yield) of the title compound ar® obtained in the form of a light-yellow powder, melting point 265~268°C.

Analysis: calc.: C 55.25 H 5.24 N 6.24 S 19.03 found: C 55.38 K 5.44 N 6.10 S 19.01 b) 14-thia-3,6,9~triazabicyclo[9.2.1]tstradeca-1(13),11diene g (66.8 mmol) of the title compound of Example 17a are introduced into 130 ml of concentrated sulphuric acid and stirred for 24 hours at 90-95^0. After cooling to o’c, 500 ml of ether are added dropwise, and the precipitate that forms is filtered off with suction and dissolved in 70 ml of 40% sodium hydroxide solution. The solution is extracted five times with 100 ml of dichloromethane each time, is dried over magnesium sulphate and is concentrated by evaporation in vacuo„ The residue is recrystallised from ether/hexane (3:1), yielding 7.8 g (55% of the theoretical yield) of the title compound in the form of a white powder.

Analysis: calc.: 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(carboxymethvl)-l4-thia-3,6,9-triazabicyclo[9.2.1 ]tetradeca-l(13) , 11-diene 7.5 g (35.5 mmol) of the title compound of Example 17b are dissolved in 45 ml of water; 13.42 g (142 mmol) of chloroacetic acid are added, and the pH is adjusted to 9.5 with 6N potassium hydroxide solution. Then the mixture is heated for 12 hours at 45-50C and the pH value is kept at 9.5-10 during' that time by the addition of further potassium hydroxide solution. After cooling to 10’C, concentrated hydrochloric acid is added until the pH reaches 2. The precipitate that forms is isolated by suction filtration and is dissolved in 100 ml of water; the solution is adsorbed on a cation exchange column (IR 120) and the column is washed with 2 litres of water and then with 0.5N ammonia solution. The ammonia fraction is concentrated by evaporation in vacuo. the residue is dissolved in 100 ml of water, and the solution is bound to an anion exchanger (IRA 67). The exchanger column is eluted with water and 0.5N formic acid. The title compound is obtained from the acid fraction by io concentration by evaporation in vacuo. For further purification, the compound is dissolved in methanol, and acetone is added until a precipitate forms. The mixture is cooled to O’c and the precipitate is filtered off with suction, yielding 7.7 g (56.3% of the theoretical yield) of the title compound in the form of a light-yellow powder.

Analysis: calc.: 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 20 d) Gadolinium complex of 3,6,9-tris(carboxymethyl )-14thia-3,6,9-triazabicyclo[9.2.1 ] tetradeca-1 (13), 11diene g (5.19 mmol) of the title compound of Example 17c are heated for 4 hours at 85-90’c with 941 mg (2.60 mmol) of gadolinium oxide in 20 ml of water. The resulting solution is filtered and is precipitated by stirring with, in succession, 0.26 g of cation exchanger (IR 120) and 0.26 g of anion exchanger (IRA 67). The solution is filtered again and is freeze-dried, yielding 2.66 g (95% of the theoretical yield) of the title compound in the form of a white amorphous powder, water content 5.7%.

Analysis: calc.: 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 (water content taken into account in the calculation) EXAMPLE 18 a) 13-methoxy-3,6,9-tris(p-tolylsulphonyl)-3,6,9,15tetraazabicyclo [9.3.1]pentadeca-l(15),11,13-triene 60.97 g (100 mmol) of the N,N-disodium salt of Ν,Ν',Νtris(p-tolylsulphonyl)diethylenetriaraine are dissolved in 800 ml of dimethylformamide, and 47.76 g (100 mmol) of 2,6-bis(p-tolylsulphonyloxymethyl)-4-methoxypyridine dissolved in 400 ml of dimethylformamide are added dropwise at 50’c over a period of 90 minutes. The mixture is stirred for 5 hours at 90eC, then 1.1 litres of water are added dropwise; the precipitate that forms is filtered off with suction and is washed with water, and the product is dried in a vacuum drying cabinet and recrystallised from isopropyl alcohol, yielding 43.3 g (62% of the theoretical yield) of the title compound in the form of a white powder.

Analysis: calc.: C 56.71 H 5.48 M 8.016 S 13.76 found: C 56.90 H 5.31 N 8.00 S 13.59 b) 13-methoxy-3,6,9,15-tetraazabicyclo[9.3 »l]pentadeca1(15),11,13-triene g (42.9 mmol) of the title compound of Example 18a are stirred for 24 hours at 95C with 100 ml of concentrated sulphuric acid. After cooling to O’C, 400 ml of ether are added dropwise and the precipitate that forms is filtered off with suction and dissolved in 60 ml of 40% sodium hydroxide solution. The solution is extracted five times with 75 ml of dichloromethane each time, is dried over magnesium sulphate and is concentrated by evaporation in vacuo. The residue is recrystallised from diisopropyl ether, yielding 6.59 g (65% of the theoretical yield) of the title compound in the form of a white powder.

Analysis: calc.: C 60.99 H 8.53 N 23.71 found: C 61.15 H 8.40 N 23.52 c) 13-raethoxy-3,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicyclof 9.3.1]pentadeca-l(15),11,13-triene 6.2 g (26.2 mmol) of the title compound of Example 18b are dissolved in 40 ml of water, and 9.90 g (104.8 mmol) of chloroacetic acid are added. The pH value is adjusted to 9.5 by the addition of 6N potassium hydroxide solution, and the mixture is heated for 8 hours at 45-50 °C. During that time, the pH value is kept at 9.5-10 by the addition of further potassium hydroxide solution. The mixture is then cooled in an ice-bath, and concentrated hydrochloric acid is added until the pH reaches 2. A precipitate forms; the precipitate is filtered off with suction, the residue is dissolved in 80 ml of water, with gentle heating, and the solution is adsorbed on a cation exchange column (IR 120). The column is eluted first with a large amount of water and then with 0.5N ammonia solution. The basic eluate is collected and concentrated by evaporation in vacuo. The residue is dissolved in 80 ml of water and the solution is adsorbed, on an anion exchange column (IRA 67). Elution is carried out first with water and then with 0.5N formic acid- The acid fraction is concentrated by evaporation in vacuo„ the residue is dissolved in methanol, and the title compound is precipitated out by the addition of acetone. 7.42 g (69% of the theoretical yield) are obtained in the form of a white powder.

Analysis: calc.: C 52.68 H 6.39 N 13.65 found: C 52.81 H 6.22 N 13.80 d) Gadolinium complex of l3-methoxy-3,6,9-tris(carboxymethyl )-3,6,9,15-tetraazabicyclo [9.3.1] pentadeca1(15) , 11,13-triene g (12.18 mmol) of the title compound of Example 18c are heated for 4 hours at 85-90°C with 2.21 g (6.09 mmol) of gadolinium oxide in 60 ml of water. The solution is filtered and freeze-dried, yielding 6.74 g (98%) of the title compound in the form of a white amorphous powder, water content 4.1%.

Analysis: calc.: 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 (water content taken into account in the calculation) EXAMPLE 19 a) 13-chloro-3,6,9-tris(tert.-butoxycarbonylmethyl)3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13triene 18.72 g (95.96 mmol) of bromoacetic acid tert.-butyl ester are added to 7 g (29.08 mmol) of the title compound of Example 5c and 10.17 g (95.96 mmol) of sodium carbonate in 200 ml of acetonitrile, and the mixture is stirred for 24 hours at room temperature.

The mixture is concentrated by evaporation jn vacuo and the residue is taken up in 300 ml of water and is extracted three times with 200 ml of methylene chloride.

After drying the organic phases over magnesium sulphate, ~ 62 Yield: 14.08 g 5 colourless oil.

Analysis: calc.: C 59.73 found: C 59.67 concentration is carried out ia vacuo and the oil that remains is chromatographed on silica gel (eluant: methylene chloride/ethanol = 15:1). (83% of the theoretical yield) of a H 8,12 M 9.61 0 16.46 Cl 6.08 H 8.25 N 9.58 Cl 6.01 b) 13-(N-pyrrolidino)-3,6,9-tris(tert.-butoxycarbonylmethyl )-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca1(15) ,11,13-triene 1.11 g (46.3 mmol) of sodium hydride (previously washed with pentane) are added carefully to 13.5 g (23.15 mmol) of the title compound of Example 19a, 3.94 g (46.3 mmol) of pvrrolidinone and 612 mg (2.32 mmol) of 18~erown~5 in 200 ml of anhydrous dimethylformamide. The mixture is stirred for 72 hours at 70°C under nitrogen. The solution is cooled to room temperature and is poured into 1.2 litres of ice-water. The mixture is then extracted three times with 250 ml of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel (eluant; methylene chloride/methanol = 13:1).

Yield: 5.7 g (39% of the theoretical yield) of a colourless oil which crystallises when left to stand.

Analysis: calc.: C 62.73 H 8.46 N 11.09 O 17.73 found: C 63.68 H 8.54 N 11.01 c) 13-(N~pyrrolidino)-3,6,9-tris(carboxymethyl)3,6,9,I5~tetraazabicyclo[9.3.1]pentadeca-l(15),11,13triene .1 g (8.07 mmol) of the title compound of Example 19b 3 are dissolved in 50 ml of trifluoroacetic acid and stirred for 6 hours at room temperature. The solvent is removed in vacuo and the product is purified over an anion exchanger as described in Example Id.

Crystallisation from MeOH/acetone yields 2.33 g (77% of 10 the theoretical yield) of a very hygroscopic substance.

Analysis; calc.: C 54.42 H 6.31 N 15.11 0 24.17 found: C 54.37 H 6.42 N 15.05 d) Gadolinium complex of l3-(Npyrrolidino)-3,6,9l 5 tris (carboxymethyl)-3,6,9,l5-tetraazabicyclc 23.3.11pentadeca-1(15),11,13-triene 2.5 g (5.4 mmol) of the title compound cf Example 19c are dissolved in 20 ml of deionised water and added to 978 mg (2.7 mmol) of gadolinium oxide. The mixture is 20 stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried.

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

Analysis: calc.: C 40.83 H 4.24 M 11.34 O 18.13 Gc 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- tetraazabicyclo[9-3.1]pentadeca-l(15) , 11,13triene g (36.01 mmol) of the title compound of Example 19a are dissolved in 200 ml of dimethylformamide, and 7.02 g (108· mmol) of sodium azide and 951 mg (3.6 mmol) of 18crown-6 are added. The mixture is stirred for 48 hours at 90*C.

After cooling to room temperature, the mixture is poured into 1.5 litres of ice-water and is extracted three times with 200 ml of ethyl acetate. After drying the organic phase over magnesium sulphate, concentration is carried out by evaporation and the oil that remains is chromatographed on silica gel (eluant: methylene chloride/ethanol = 15:1) .

Yield: 10.83 g (51% of the theoretical yield) of a pale yellow oil.

Analysis: calc.: 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. -butoxycarbonyImethyl) 3.6.9.15- tetraazabicyclo [9.3.1]pentadeca-l( 15),11,13triene g (16.96 mmol) of the title compound of Example 20a are dissolved in 400 ml of ethanol and added to X g of Pearlman catalyst (20% palladium hydroxide on carbon). After hydrogenation for 24 hours under normal pressure, the catalyst is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oil that remains is chromatographed on silica gel (eluant: methylene chloride/methanol/triethylamine = 10:1:0.05), yielding 8.89 g (93% of the theoretical yield) of a slightly yellowish oil.

Analysis: calc.: 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-tefcraaza bicyclo[9.3.1]pentadeca-1(15),11,13-triene 8.2 g (14.55 mmol) of the title compound of Example 20b are dissolved in 100 ml of trifluoroacetic acid and stirred for 6 hours at room temperature. After removal of the solvent by evaporation in vacuo. the residue is dissolved in 100 ml of water and passed over a column filled with poly(4-vinylpvridine). Concentration by evaporation in vacuo and crystallisation from methanol/ acetone yield 5.24 g (91% of the theoretical yield) of very hygroscopic solid.

Analysis: calc.: 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-tetraazabicyclo[9.3.1]pentadeca1(15),11,13-triene 4.8 g (12.14 mmol) of the title compound of Example 20c are dissolved in 35 ml of deionised water and added to 2.2 g (6.07 mmol) of gadolinium oxide. The mixture is stirred for 3 hours at 90C and the pH value is kept at .5 by the addition of acetic acid. The solution is filtered and passed over a column filled with poly(4vinylpyridine). After treatment with activated carbon, the mixture is filtered again and is freeze-dried. Yield: 6.07 g (91% of the theoretical yield) of an amorphous powder which, contains 12.1% water.

Analysis: calc.: C 37,15 H 4,06 found: C 37.08 H 4.17 according to the analysis, N 12.74 0 17.47 Gd 28.61 N 12.68 Gd 28.54 EXAMPLE 21 a) 13-(hydroxvacetamido )-3,6,9-tris (tert. -.butoxycarbonyl methyl )-3,6,9,15-tetraazabicyclo [9.3.1Jpentadeca1(15),11,13-triene .8 g (10.28 mmol) of the title compound of Example 20b, 861 mg (11.32 mmol) of glycolic acid and 1.53 g (11.32 mmol) of 1-hydroxy-lH-benzotriazole hydrate are dissolved in 20 ml of absolute dimethylformamide and cooled to 0’C. 2.36 g (11.32 mmol) of dicyclohexylcarbodi imide are added, and the mixture is stirred for one hour at 0°C and then overnight at room temperature. The solution is added to 150 ml of ice-water and is extracted three times with 150 ml of ethyl acetate. After drying the organic phase over magnesium sulphate, concentration is carried out by evaporation in vacuo. The residue is chromatographed on silica gel (eluant: methylene chloride/methanol = 10:1).

Yield: 2.88 g (45% of the theoretical yield) of a colourless solid.

Analysis: calc.: C 59.88 H 8.27 N 11.26 O 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 [ 9.3.1]pentadeca-l(15),11,13 triene 2.7 g (4.34 mmol) of th© title compound of Example 21a are dissolved in 40 ml of trifluoroacetic acid and stirred for 6 hours at room temperature. The mixture is concentrated hy evaporation jn vacuo and the residue is purified over an anion exchanger as described in Example id.

Crystallisation from isopropanol yields 1.56 g (79% of the theoretical yield) of a white powder.

Analysis: calc.: C 50.32 H 6.00 N 15.45 O 28.23 found: C 50,24 H 6.07 N 15.49 c) Gadolinium complex of 13-(hydroxyacetamido)-3,6,9tris(carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca~l(15),11,13-triene 1.45 g (3.2 mmol) of the title compound of Example 21b are dissolved in 10 ml of deionised water and added to 580 mg (1.6 mmol) of gadolinium oxide. The mixture is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried.

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

Analysis: calc.: C 37.55 H 3.98 N 11.53 O 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-tolylsulphonyl)-3,6,9-triazabicyclo[9.3.1]pentadeca-l(15),11,13-triene 182.85 g (300 mmol) of the. N,Nw-disodium salt of Ν,Ν',Ν8tris(p-tolylsulphonyl)diethylenetriamine are dissolved in 2.4 litres of dimethylformamide and heated to 100°C. A solution of 63.15 g (300 mmol) of 4-chloro-2,6-bis(chloromethyl)pyridine in one litre of dimethylformamide is added dropwise over a period of 3 hours. The mixture is stirred overnight at 100°C. 3 litres of water are added dropwise to the solution while it is still hot, and the mixture is cooled to room temperature. The precipitate is washed with a large amount of water and is dried in vacuo, (60*0). Crystallisation from, acetonitrile yields 128.7 g (61% of the theoretical yield) of the title compound in the form of a colourless powder.

Analysis: calc.; 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 )5 p) i3-(N-morpholino)-3,6,9-tris(p-tolylsulphonyl)-3,6,9triazabicyclo[9.3.1]pentadeca-1{15),11,13-triene 126 g (179 mmol) of the title compound of Example 22a are dissolved in 500 ml of dimethyl sulphoxide and added to 87.12 g (1 mol) of morpholine. The solution is 2o stirred in an autoclave for 48 hours at 140 °C and 10 bar. The mixture is cooled and poured onto 3 litres of water, and the precipitate is filtered off with, suction. After drying in vacuo at 60°C, the product is recrystallised from acetone, yielding 87.72 g (65% of th® theoretical yield) in the form of a cream-coloured powder.

Analysis: calc.; C 57.35 H 5.,75 N 9.29 O 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-tetraazabicyclo30 [9.3.l]pentadeca-l(15),11,13-triene S6 g (114 mmol) of the title compound of Example 22b are introduced into 270 ml of concentrated sulphuric acid and stirred for 48 hours at 100’c. The mixture is cooled to 0‘c, and 1.35 litres of absolute ether are added dropwise. The precipitate is filtered off with suction and suspended in 100 ml of aqueous sodium hydroxide solution (pH 12). The mixture is extracted seven times with 150 ml of chloroform and the combined organic phases are dried over magnesium sulphate. Concentration by evaporation in vacuo yields 22.26 g (67% of the theoretical yield) of a yellowish oil, which crystallises when left to stand.

Analysis: calc.: C 61.82 H 8.65 N 24.04 0 5.49 found: C 61.89 H 8.59 N 24.13 d) 13-(M-morpholino)-3,6,9-tris (carboxymethyl )-3,6,9,15tetraazabicyclo [ 9 .3.1]pentadeca-l( 15) , ll,13-triene g (34.3 mmol) of the title compound of Example 22c are dissolved in 150 ml of water and added to 12.85 g (136 mmol) of chloroacetic acid. The pH is adjusted to 9.5 with 6N potassium hydroxide solution. The mixture is stirred for 12 hours at 45’c and the pH value is kept at 9.5-10 by the addition of 6N potassium hydroxide solution. The pH is adjusted to 2 with concentrated hydrochloric acid and the mixture is purified over ion exchangers as described in Example id. Crystallisation from methanol/acetone yields 9.9 g (62% of the theoretical yield) of the title compound in the form of a very hygroscopic solid.

Analysis: calc.: C 54.18 H 6.71 N 15.05 0 24.06 found: C 54.09 H 6.82 N 15.01 e) Gadolinium complex of 13-(N-morpholino)-3,6e9-tris(carboxymethyl )-3,6,9,15-tetraazabicyclo [9.3.1] pentadeca-1 (15),11,13-triene g (19.33 mmol) of the title compound of Example 22d 5 are dissolved in 60 ml of deionised water and added to 3.5 g (9.67 mmol) of gadolinium oxide. The mixture is stirred for 3 hours at 90C and the pH value is kept at .5 by the addition of acetic acid. The solution is filtered and passed over a column filled with poly(410 vinylpyridine). After treatment with activated carbon, the product is filtered again and is freeze-dried.

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

Analysis: calc.·. 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-tetraazabi2 0 cyclo[9.3.1]pentadeca-1(15),11,13-triene 9.3 g (38.62 mmol) of the title compound of Example 5c and 21.36 g (154.5 mmol) of potassium carbonate are dissolved in 200 ml of dimethylformamide and heated to 70C. 26.43 g (154.5 mmol) of benzyl bromide are added 25 dropwise over a period of 30 minutes, and th© mixture is stirred for 24 hours at 70‘e.

The solvent is removed in vacuo and the residue is taken up in 250 ml of 3N sodium hydroxide solution. Th© mixture is extracted five times with 150 ml of methylene chloride and th© organic phases are dried over magnesium sulphate. After concentration by evaporation jn. vacuo,. the residue is chromatographed on silica gel (eluant: isopropanol/triethylamine = 20:1).

Yield: 17.97 g (91% of the theoretical yield) of a pale yellow oil.

Analysis: calc.: 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 fo) 13-carhoxv-3,6,9-tris(benzyl)~3,6,9,15-tetraazafoicyclo[9.3.1]pentadeca-l(15),11,13-triene io a solution of 17.5 g (34.24 mmol) of the title compound of Example 23a in 80 ml of 1,2-dimethoxyethane is added dropwise to 1.95 g (79.44 mmol) of magnesium turnings, and the mixture is heated to boiling. A solution of 6.43 g (34.24 mmol) of 1,2-dibromoethane in 40 ml of 1,215 dimethoxyethane is added dropwise over a period of 12 hours.

The mixture is cooled in an ice-bath, and the solution is poured carefully onto 10 g of dry ice. After stirring for 3 hours at room temperature, 200 ml of water are 20 added carefully and the pH is adjusted to 4 with hydrochloric acid. The mixture is concentrated to dryness by evaporation and the residue is extracted by boiling with 200 ml of ethanol. After removal of the magnesium salts by filtration, concentration to dryness is carried out again by evaporation, and the residue is chromatographed on silica gel (eluants chloroform/methanol/triethylamine = 20:15:1).

Yield: 5.16 g (29% of the theoretical yield) of a pale yellow solid30 Analysis: calc.: C 76.27 H 6.79 N 10.78 0 6.16 found: C 76.19 H 6.88 M 10.71 c) 13-(morpholinocarbonyl)-3, δ,9-tris(benzyl)-3,6,9,15tetraazabicyclo[ 9.3.1]pentadeca-l(15),11,13-triene .0 g (9.62 mmol) of the title compound of Example 23b, 922 mg (10.58 mmol) of morpholine and 1.43 g (10.58 mmol) of 1-hydroxy-lH-benzotriazole hydrate are dissolved in 10 ml of absolute dimethylformamide and cooled to O’C. 2.18 g (10.58 mmol) of dicyclohexylcarbodiimide ar® added, and the mixture is stirred for one hour at 0’C and then overnight at room temperature.

The solution is poured into 180 ml of ice-water and extracted three times with 150 ml of chloroform. After drying the organic phase over magnesium sulphate, concentration is carried out in vacuo. The residue is chromatographed on silica gel (eluant: chloroform/15 methanol/triethylamine = 20:5:1), yielding 4.22 g (88% of the theoretical yield) of the title compound in the form of a colourless oil.

Analysis: calc.: C 75.48 H 7.19 N 11.90 0 5.44 found: C 75.37 H 7.27 M 11.83 d) 13-(morpholinocarbonyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),11,13-triene 4.1 g (6.96 mmol) of th® title compound of Example 23c are dissolved in 250 ml of ethanol and added to 0.5 g of Pearlman catalyst (20% palladium hydroxide on carbon). After hydrogenation for 24 hours in an autoclave (50’c and 3 bar hydrogen pressure), the catalyst is filtered off with suction and the filtrate is concentrated in vacuo. The residue is recrystallised from 30 ml of o tetrahydrofuran.

Yield: 1.85 g (83% of the theoretical yield) of the title compound in the form of a white crystalline powder. - 73 Analysis: calc.: 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) 5 3,6,9,15-tetraazabicyclo[ 9.3.1] pentadeca-1 (15),11,13triene 1.6 g (5.0 mmol) of the title compound of Example 23d are dissolved in 25 ml of water and added to 1.89 g (20 mmol) of chloroacetic acid. The pH is adjusted to 9.5 10 with 6N potassium hydroxide solution. The mixture is stirred for 12 hours at 45’C and the pH value is kept at 9.5-10 by the addition of SN potassium hydroxide solution.

After working up over ion exchangers as described in Example Id, crystallisation from methanol/acetone yields 1.66 g (67% of the theoretical yield) of a very hygroscopic solid.

Analysis: calc.: 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)-3,6,9tris(carboxymethyl)-3,6,9,IS-tetraazabicyclo[9=3.1]pentadeca-l(15),11,13-triene 1.5 g (3.04 mmol) of the title compound of Example 23e are dissolved in 10 ml of deionised water and added to 551 mg (1.52 mmol) of gadolinium oxide. The mixture is stirred, for 3 hours at 90 °C. The solution is filtered and the filtrate is freeze-dried.

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

Analysis: calc.: 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 for in vivo NMR diagnostics: Following the recording of a pre-image using a nuclear spin tomograph (manufacturer: General Electric, 2 tesla), 0.1 mmol of the gadolinium complex of 3,6,9-tris(carboxy5 methyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca1(15) ,11 13-triene [Example le] per kg was administered, i.v. into a caudal vein of a naked female Balb/c nu/nu mouse weighing 20 g and having a subcutaneous MT 29 colon carcinoma. The substance was dissolved in bi10 distilled water (pH 7.2). Images were recorded in the spin-echo sequence Tr = 400 msec.( Te = 30 msec..

The images were recorded before and 1, 23 and 43 minutes after administration of the contrast agent in the region of the liver and of the tumour.

It was possible to demonstrate that the signal intensity in the tumour rose and did not fall again over the period observed.

The figure shows a transverse section of a naked Balb/c nu/nu mouse having an HT 29 colon carcinoma before and after the i.v. administration of the contrast agent. The images were recorded in the spin-echo sequence Tr = 400 msec., Te = 30 msec..

The top left of the image shows the mouse before administration of the contrast agent. The image shows the liver and the subcutaneous tumour. The other images were recorded 1, 23 and 43 minutes after administration.

Claims (12)

1. 1. Macrocyclic compounds of the general formula I z wherein .... represents a single bond or a double bond, q represents the numbers 0 to 5, A and B, which are the same or different, each represent a straight-chained or branched alkylene group having from

2. To 6 carbon atoms, D represents a nitrogen atom, an oxygen atom, the group =C=O, =NR 2 , -CHR 3 - or =CR 3 -, E represents a nitrogen atom, a sulphur atom, an oxygen atom, the group =N(*)-, =C- or >NR 4 , i() OH, F represents (~CHR 8 -)n or (=CR s )n, R 1 represents a hydrogen atom or a halogen atom or a Ci-Cg-alkyl group, Z represents a hydrogen atom or the group -Ci^COOY wherein Y represents 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, R 2 represents a hydrogen atom or a C^-Cg-alkyl group, R 3 represents a hydrogen atom or a halogen atom, a phenyl group or a C^-Cg-alkyl group optionally substituted by one or more phenyl and/or hydroxy groups, or represents the radical OR 5 , the substituent -(C)iNR s R 7 or Β “ O the substituent G, R 4 represents a hydroxy group, R 2 or an optionally hydroxylated or carboxylatad C^-Cg-alkyl group, R 5 represents a C^-Cg-alkyl radical optionally substituted by from 1 to 3 hydroxy groups, R 8 and R 7 , independently of each other, represent hydrogen atoms, the radical R 5 , or phenyl or benzyl radicals optionally substituted by from 1 to 3 hydroxy groups, or R 5 and R 7 , together with the nitrogen atom, form a saturated or unsaturated 5- or 6-membered ring that optionally contains a further nitrogen, oxygen or sulphur atom or a carbonyl group and that is optionally substituted by from 1 to 3 radicals R 5 , or one of the substituents R 6 and R 7 represents the radical 11 s -C-R 5 , R 8 represents R 1 or G, 1 represents the number 0 or 1, n represents the number 0 or 1, G represents a second macrocycle of the general formula XI that is bonded via a direct bond, a bis(carbonylamino) group (~NK-CO-CQ~HH~) or via a C 1 -C20“alkylene group that optionally carries carbonyl (>C0) or carbony lamino (-ΝΉ-CG-) groups or oxygen atoms at the ends and that optionally contains one or more oxygen atoms, 2-, acyl- or hydroxyacyl-substituted imino groups or one or two c-C-double and/or C-C-triple bonds: A I M - 3 ) Z wherein D- has the same meaning as D, contain the substituent G, except that D 1 does not or D“ represents the (II) radical -CH-, =C- or -N-, and F 1 has the same meaning as F, except that F~ does not contain the substituent G, or F- represents the radical -CH- or =C- Z 5 and their salts with inorganic and/or organic bases, amino acids or amino acid amides, with the provisos that at least two of the substituents Z represent the radical -CH 2 COOY, that the macrocyclic compound of the general formula I does not contain more 10 than one radical G, and that the general formula I does not represent 3,6,9,i2,18~pentaazabieyclo[12.3.1]octa~ deca-1(18),14,16-triene-N-tetraacetic acid or 3,6,9,15tetraazabicvclo[9.3.1 ]pentadeca-1 (15),11,13-triene-Ntriacetic acid or their Cu, Pb, Co and Sr complexes. 15 2. Compounds according to claim l, characterised in that Y represents hydrogen atoms.

3. Compounds according to claim 1, characterised in that at least two of the substituents Y are metal ion equivalents of at least one element of atomic numbers 21-29, 20 42, 44 or 57-83 or of at least one radionuclide of an element of atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77.

4. Compounds according to claim 1, characterised in that G represents a ring of the general formula II that is 25 bonded via a group -(0Η 2 )χ„ 6 -, -0-(CH 2 )7-5-0-, 00 0 0 I II 1 II -C-(CH 2 ) x^g-C-,, -C=C-C=C“ or -NH-C-(CH 2 ) 0 _ 6 ~C-NH- .

5. Pharmaceutical agents comprising at least one physiologically tolerable macrocyclic compound of the general formula 1 SO Ο / A (N-8 1 (I) wherein .. represents a single bond or a double bond, q represents the numbers 0 to 5, A and B, which are the same or different, each represent a straight-chained or branched alkylene group having from 2 to 6 carbon atoms, D represents a nitrogen atom, an oxygen atom, the group =C=O, =NR 2 , -CKR 3 - or =CR 3 -, Ξ represents a nitrogen atom, a sulphur atom, an oxygen atom, the group =^(^)-, =C- or >NR 4 , 0(-) OH, F represents (-CHR 8 -^ or (=CR 8 ) n , R 1 represents a hydrogen atom or a halogen atom or a Cj-Cg-alkyl group, Z represents a hydrogen atom or the group -C^COOY wherein Y represents 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, R 2 represents a hydrogen atom or a Cb-Cg-alkyl group, R 3 represents a hydrogen atom or a halogen atom, a phenyl group or a C^-Cg-alkyl group optionally substituted by one or more phenyl and/or hydroxy groups, or represents the radical OR 5 , the substituent -(C) ηNR 6 R 7 or 15 “ the substituent G, R 4 represents a hydroxy group, R 2 or an optionally hydroxylated or carboxylated C^-Cg-alkyl group, R 5 represents a Cb-Cg-alkyl radical optionally substituted by from 1 to 3 hydroxy groups. R 6 and R 7 , independently of each other, represent hydrogen atoms, the radical R 5 , or phenyl or benzyl radicals optionally substituted by from 1 to 3 hydroxy groups, or R 6 and R 7 , together with the nitrogen atom, form a saturated or unsaturated 5- or 5-membered ring that optionally contains a further nitrogen, oxygen or sulphur atom or a carbonyl group and that is optionally substituted by from 1 to 3 radicals R 5 , or one of the substituents R s and R 7 represents the radical ~C~r5, R 8 represents R 1 or G, 1 represents the number 0 or 1, n represents the number 0 or 1, G represents a second macrocycle of the general formula II that is bonded via a direct bond, a bis(carbonylamino) group (-NH-CO-CO-NH-) or via a. C 1 -C 20 “ a lkylene group that optionally carries carbonyl (>CO) or carbonylamino (-NH-CO-) groups or oxygen atoms at the ends and that optionally contains one or more oxygen atoms, 2-, acyl- or hydroxyacyl-substituted imino groups or one or two C-C-double and/or C-C-triple bonds: Z-N N-Z (II) x (N-3 ) I q z wherein D 1 has the same meaning as D, except that D 1 does not contain the substituent G, or D 1 represents the l I I radical -CH-, =C- or -N-, and F- has the same meaning as P, except that F- does not contain the substituent G, or F 1 represents the radical H- or and their salts with inorganic and/or organic bases, amino acids or amino acid amides, with the provisos that at least two of the substituents z represent the radical -CH2COOY, and that the macrocyclic compound of the general formula I does not contain more than one radical G, optionally together with additives customary in galenic pharmacy.

6. Use of at least one physiologically tolerable compound of the general formula I z wherein represents a single bond or a double bond, q represents the numbers 0 to 5, A and B, which are the same or different, each represent a straight-chained or branched alkylene group having from 2 to 6 carbon atoms, D represents a nitrogen atom, an oxygen atom, the group =C=O, =NR 2 , -CHR 3 - or =CR 3 -, Ξ represents a nitrogen atom, a sulphur atom, an oxygen atom, the group -N ( + ), =C- or >NR 4 , o(“) OH, F represents (-CHR 8 -)n or (~CR ? ')n, R 1 represents a hydrogen atom or a halogen atom or a C^-Cg-alkyl group, Z represents a hydrogen atom or the group -CHgCOOY wherein ¥ represents 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, R 2 represents a hydrogen atom or a C^-Cg-alkyl group, R 3 represents a hydrogen atom or a halogen atom, a phenyl group or a Gj^-Cg-alkyl group optionally substituted by one or more phenyl and/or hydroxy groups, or represents the radical OR 5 , the substituent -(C)iNR®R 7 or U ~ O the substituent G, R 4 represents a hydroxy group, R 2 or an optionally hydroxylated or carboxylated C^-Cg-alkyl group, R 5 represents a C^-Cg-alkyl radical optionally substituted by from 1 to 3 hydroxy groups, R 6 and R 7 , independently of each other, represent hydrogen atoms, the radical R 5 , or phenyl or benzyl radicals optionally substituted by from 1 to 3 hydroxy groups, or R 6 and R 7 , together with the nitrogen atom, form a saturated or unsaturated 5- or 6-membered ring that optionally contains a further nitrogen, oxygen or sulphur atom or a carbonyl group and that is optionally substituted by from 1 to 3 radicals R 5 , or one of the substituents R 6 and R 7 represents the radical 11 r -C-R 5 , r 8 represents R 1 or G, 1 represents the number 0 or l, n represents the number 0 or l, G represents a second macrocycle of the general formula II that is bonded via a direct bond, a bis(carbonylamino) group (-HH-CO-CO-NH-) or via a Ci-C 2 o“alkylene group that optionally carries carbonyl (>CO) or carbonylamino (-NH-CO-) groups or oxygen atoms at the ends and that 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: (II) wherein D~ has the same meaning as D, except that D 1 does not contain the substituent G, or D 1 represents the I i l radical -CH-, =C~ or -N-, and F 1 has the same meaning as F, except that F 1 does not contain the substituent G, or F 1 represents the radical -CH- or =C~, and their salts with inorganic and/or organic bases, l o amino acids or amino acid amides, with the provisos that at least two of the substituents Z represent the radical -CH^COOY, that the macrocyclic compound of the general formula I does not contain more than one radical G, and that at least two of the substi15 tuents Y are metal ion equivalents of at least one element of atomic numbers 21-29, 42, 44 or 57-83 or of at least one radionuclide of an element of atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77, for the preparation of agents for NMR, X-ray or radio20 diagnostics, radiotherapy or radiation therapy.

7. Process for the preparation of macrocyclic compounds of the general formula I wherein represents & single bond or a double bond, q represents the numbers 0 to 5, A and 3, which are the same or different, each represent a straight-chained or branched alkylene group having from 2 to 6 carbon atoms, D represents a nitrogen atom, an oxygen atom, the group =C=O, =NR 2 , -CHR 3 - or =CR 3 -, E represents a nitrogen atom, a sulphur atom, an oxygen atom, the group =C- or >NR 4 , O () OH, F R 1 represents (-CHR 8 -)n or (=CR 8 )n, represents a hydrogen atom or a halogen atom or a Ci-Cg-alkyl group, Z represents a hydrogen atom or the group -CH2COOY wherein Y represents 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, R 2 represents a hydrogen atom or a C^-Cg-alkyl group, represents a hydrogen atom or a halogen atom, a phenyl group or a Cx-Cg-alkyl group optionally substituted by one or more phenyl and/or hydroxy groups, or represents the radical OR 5 , the substituent -(C)xNR 6 R 7 or O the substituent G, R 4 represents a hydroxy group, R 2 or an optionally hvdroxylated or carboxylated Cx-Cg-alkyl group, R 5 represents a Cj-Cg-alkyl radical optionally substituted by from 1 to 3 hydroxy groups, R 6 and R 7 , independently of each other, represent hydrogen atoms, the radical R 5 , or phenyl or benzyl radicals optionally substituted by from 1 to 3 hydroxy groups, or R 6 and R 7 , together with the nitrogen atom, form a saturated or unsaturated 5- or 6-membered ring that optionally contains a further nitrogen, oxygen or sulphur atom or a carbonyl group and that is optio- ss nelly substituted by from 1 to 3 radicals R 5 , or one of the substituents R 6 end R z represents the radical ΐ 5 -OR 5 , R 8 represents R- or G, 1 represents the number 0 or I, n represents th® number 0 or 1, G represents a second macrocycle of the general formula II that is bonded via a direct bond, a bis(carbonylamino) group (-HB-CO-CO-NH-) or via a c l“ c 20“ alk y lens group that optionally carries carbonyl (>CO) or carbonylamino (-MS-CO-) groups or oxygen atoms at the ends and that 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: (II) wherein D- has the same meaning as D, except that D- does not contain the substituent G, or D~ represents the I I I radical -GH-, ~C- or and F 1 has th© sane meaning as F, except that F 1 does not contain the substituent G, or F- represents the 8. Ι radical -CH- or =C-, and their salts with inorganic and/or organic bases, amino acids or amino acid amides, with the provisos that at least two of the substituents Z represent the radical that the aacr©cyclic compound of the general formula I does not contain more than one radical G, and that the general formula I does not represent 3,6,9,12,18-pentaazabicyclo[l2.3.l]octa“ deca-l(18) ,14,16-triene-M-tetraacetic acid or 3,6,9,15tetraazabicyclo [9.3.1 ] pentadeca-l (15),11,13-triene-N5 triacetic acid or their Cu, Pb, Co and Sr complexes, characterised in that compounds of the general formula I' H-N I A· N-H \,N. 8) (I')r wherein X represents or a 5- or 6-membered ring for conversion into the desired ring, are alkylated in a manner known per se with compound III a halogen HalCH 2 COO¥ (III), wherein Hal represents chlorine, bromine or iodine and 15 y·’ represents a hydrogen atom or an acid-protecting group, and then, where appropriate after conversion of X into the desired 5- or δ-membered ring of the end product and, where appropriate, after removal of the protecting groups 20 , the resulting complexing agents of the general formula I wherein Y represents hydrogen are, if desired, reacted in a manner known per se with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 Or 57-83 and then, if 25 desired, any acidic hydrogen atoms that are still present . are replaced with cations of inorganic and/or organic bases, amino acids or amino acid amides.

8. Process for the preparation, of the pharmaceutical agents according to claim 5, characterised in that the complex compound dissolved or suspended in water or physiological saline solution, optionally together with 5 additives customary in galenic pharmacy, is brought into a form suitable for enteral or parenteral administration.

9. A compound substantially as hereinbefore described with reference to the Examples.

10. A pharmaceutical agent substantially as hereinbefore 10 described with reference to the Examples.

11. A use substantially as hereinbefore described with reference to the Examples.

12. A process substantially as hereinbefore described with reference to the Examples.