IE892335L - Macrocyclic polyaza compounds containing 5 or 6 rings,¹process for producing them and pharmaceutical media¹containing them - Google Patents

Abstract

Macrocyclic compounds of the general formula I 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 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 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 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 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 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

6 6 6 9 3 - i - The invention relates to the subject characterised in the patent claims, that is to say to macrocyclic polyaza complexing agents c complexes and complex salts containing a 5~ or S-memberad ring, to agents containing those 5 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. 10 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 15 purposes could be considered. As the foremost representative of this class of substances, the dimeglusaine salt of Gd DTPA (gadolinium(IIl) complex of diethylenetri-aminepentaacetic acid), which is described in the European Patent Application having the publication number 20 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 2 5 in clinical use is.its high degree of effectiveness in nuclear spin tomography, especially in the 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 30 in many X-ray examinations.

As a further representative of the complex salts, the meglumine salt of Gd DOTA (gadolinium(III) complex of 1,4,7,lo-tetr&azacyclododecanetetraacetic acid), which is - 2 - / 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 5 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 20 stability, the contrast-heightening effect, the tolera- bilitv 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 2 5 a process for their preparation that is as siaaple 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 30 requirements in a surprising manner, They possess a. 3 - 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. 5 relaxivity) and/or tolerability (e.g. fewer cardio vascular or allergic side-effects) than do the hitherto conventional diagnostic agents.

Even without specific measures, their pharmacokinetics permits improved diagnosis of numerous disorders. The >0 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 15 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, 20 the selection of a variety of substituents, of the 5™ or 6-membered ring in the macrocycle and,/or of the salt-forming substances allows the properties to be adapted to requirements as regards effectiveness, pharmacokinetics, tolerability,, solubility, handling,, etc-. For 2 5 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. 30 The macrocyclic compounds according to the invention are characterised by the general formula I: - 4 - J; jJ— I Z-M H-Z (X) H- (H-0 I wherein j . represents a single bond or a double bond,, q represents the numbers 0 to 5, 5 A and B, which are the same or different, each represent a straight-chained, or branched alkvlene group having from 2 to s carbon atoms, D represents a nitrogen atom, an oxygen atom, the group ~C=Op =m2f -CER-*- or =CR3~, LO E represents a nitrogen atom, a sulphur atom, an oxygen atom, the group =H(+)-, =C- or >NR4, o(~^ OH, F represents (~CERa-)n or (=CRa)n, R1 represents a hydrogen atom or a halogen atom or a cl~c6-alkyl group, 15 2 represents a hydrogen atom or the group -CHjCOOY 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, R2 represents a hydro-gen atom or a C^-Cg-alkyl group, 20 R3 represents a. hydrogen ©ton or a halogen atom, a phenyl group or a O^-Cg-alky! group optionally substituted by one or more phenyl and/or hydroxy groups, or represents the radical OR5, the substituent -(C)iMR®R/ or o the substituent G, 25 R4 represents a hydroxy group, R2 or an optionally hydroxylated or carbooeylated C^-Cg-alkyl group, R5 represents a C^-Cg-alkyl radical optionally substituted by fro* l to 3 hydroxy groups. - 5 - ] 0 15 20 25 "D 8 AX 1 n G R5 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 6-raexnbered 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 or one of the substituents R6 and R7 represents the radical 0 11 * -CHR5, represents R1 or G, represents the number 0 or 1, represents the number 0 or 1, represents a second macrocycle of the general formula XI that is bonded via a direct bond, a bis(carbonylami no) group (-NH-CO-CO-NH-) or via a Ci-C20-al]cylene 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~, acvl- or hydroxyacyl-substi-tuted ixaino groups or one or two C-C-dou.ble and/or C-C-triple bonds: (ID wherein D1 has the same meaning as D, except that D1 does not contain the substituent G, or D1 represents the I I 1 radical -CH-, =C- or -N~, and F1 has the sane meaning as F, except that F1 does not contain the substituent G, or F1 represents the - 6 - radical -CH- or - When n is the number 0 and the 5-raeiabered 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. 15 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 20 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 25 use in NMR diagnostics f 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) „ 30 iron(II), cobalt(II), nickel(II), copper(II), praseodym-(III) „ neodym(III), samarivun( III) and ytterbium(III) - 7 ~ ions. The gadolinium(III), terbium(III), dysprosium-(III), holmium(III) , erbium(IIX) and iron(ITi) ions are especially preferred on account of their very strong magnetic moment. 5 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, cobaltf gallium, germanium, yttrium, strontium, technetium, indium, ytterbium, gadolinium, 10 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 lanthanuia(III) ion and the above-mentioned 20 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 2 5 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. r There may be mentioned as optionally substituted alkyl 30 groups, for example, the groups methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-hydroxy~l-(hydroxymethyl)-ethyl, 1-(hydroxymethyl)-ethyl, propyl, isopropyl, 2- and 3- - 8 - hydroxypropyl, 2 , 3-dihydroxypropyl, n-, sec. - and tert.- butyl, 2-, 3- and 4-hydroxybutyl, 2- and. 3~hvdroxyiso-butyl, pentyl, 2-, 3- and 4-hydroxy-2-methylbutyl, 2,3,4-trihydroxybutyl, l, 2,4-trihydroxybu.tyl, cvclopentyl, 5 cyclohexyl, 2,3,4,5,6~pentahydroxyhexyl, benzyl, carboxy- methyl and carboxyethyl.

There may be mentioned as a halogen atom contained in R1 and R3 fluorine, chlorine, bromine and iodine.

The heterocyclic 5- or 6-raambered ring formed by R6 and 10 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 hetero-15 cycles: the pvrrolidinyl, piperidyl, pyrazolidinyl, pyrrolinyl, pvrasolinyl, piperazinyl, xaorpholinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl and pyrroli-donyl rings.

Suitable alkylene groups A and 8 are straight-chained or 20 branched chains having from 2 to 6 carbon atoms, preferably the ethylene, methyiethylene and propylene groups.

The alkylene chain to which the second macrocycle II is bonded optionally carries carbonyl (CO) or carbony1amino (MH-CQ) groups or oxygen atoms at the ends and contains 25 from 1 to 20 carbon atoms. It may be interrupted by on© or more oxygen atoms, Z-, acyl- or hydroxyacyl-suhstifctrced 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 30 hydroxy1ated acyl groups are acyl radicals having up to 10 carbon atoias. The acetyl, propionyl, kutyryl, benzoyl - 9 - and hydroxyacetyl radicals :may toe 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 carboxymethy1imino groups™ Examples of the alkylene chain are: -(CH2 ) 2- , -CH2-0-CH2-, - ( C H 2 I f - , - (CH2-CH2-0-CH2-CH2)-, - -(CH2-0-CH2)3-, -CH2-CH2-(0-CH2-CH2)3-, -CH2-CH2-(0-CH2-CH2)t-, -CH^CH- OH OH 0 0 I II II -CH-CH-, -CH -C-. -CH _-CH-CH-CH„-, -C=C-C=C-, -NH-C-(CH ) ,-C-NH || 2 | 1 I I £ 1 " & OH OH CH -C00H OH OH 0 II •CH2-N-CH2~CH2-N-CH2-CH2-N-CH,~, -C-(CH2)t„g-C-, -0-(CH2) ,.6-0- . h K C00H C00H C00H -CH2-N~CH2- , - The macrocyclic complexes of the general formula X according to the invention are prepared as follows: compounds of the general formula I" j—x 1 H-N N-H L J d'), ( N - 9 ) i q H wherein X represents conversion into the desired ring, are alkylated in a manner known per se with a halogen compound III HalCH2COOY" (III), wherein Hal represents chlorine, bromine or iodine and ¥' represents a hydrogen atom or an acid-protecting group, and then, where appropriate after conversion of X into the desired 5- or S~msmhered ring of the end product and e, where appropriate, after removal of the protecting groups Y', 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 desired, any acidic hydrogen atoms that are still present are replaced with, cations of inorganic and/or organic - IX - bases, amino acids or amino acid amides.

Suitable acid-protecting groups Y' are lover alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, n-hutyl,, tert.-butyl, phenyl, benzyl, diphenyl-5 methyl, triphenylmethyl and bis(p-nitrophanvl)methyl groups, as well as trialkylsilyl groups.

The removal of the protecting groups Y', 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 10 effected according to the processes known to the person skilled in the art,, for example by hydrolysis, hydrogeno-lysis, alkaline hydrolysis of the esters with alkali in aqueous-alcoholic solution at temperatures of from 0 to 50"c or, in the case of, for example, tert.-butyl esters, 15 with the aid. of trifluoroacetic acid.

The alkylation of the starting materials I' with the halogen compounds of the general formula III is carried out in palax aprotic solvents such as, for example, dimethylformanide, acetonitrile, dimethyl sulphoxide, 20 aqueous tetrahydrofuran or hexamethylphosphoric acid triamide in the presence of an acid acceptor, such as, for example, a tertiary amine (e.g. triethylaraine, tri-methy1amine, NyH-diaethylaminopyridine, 1,5-diazabicyclo-[4.3.0]non-5-ene (DBN), 1,5-diazabicyclo[5.4.0]undec-5~ 2 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 C"C to 50"c. 30 The conversion of a precursor of the desired 5- or 6- membered ring contained in the end product is carried out according to the methods known to the person skilled in - 12 - the art. There may be mentioned by way of example the hydrogenation of, for example, pyridine rings [Advan. Catal. JJ., 203 (19.63)], pyrrol® rings [M. Freifelder, Practical Catalytic Hydrogenation, 577, Wiley-Inter-5 science, Sew York-London-Sydney-Toronto 1371], furan rings [US~3,194,818] and pyrimidine rings [J. Med. Cham. 15, 291 (1972)], the deoxygenation of nitroxide rings [E. Klingsberg, The Chemistry of Heterocyclic Compounds, Volume 14, part 2, Interscience Publishers New York, 10 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 15 Compounds,, Volume 14, Part 2, Interscience Publishers Mew York, p. 341 (1961), Houben-Weyl, Methoden der organi-schen Cheraie, Volume V/3, 651 (1962)], the exchange of hetero atoms, for example the conversion of a furan into a pyrrole (US~2,478,456). 2 0 The functionalisation of 4-chloropyridine derivatives (e.g. azide exchange) in the phase transfer process using 18-cro%m-S or tetrsbutyl ammonium bromide as catalyst is described in "Phase Transfer Reactions3' (Fluka Compendium Vol. 2; Walter E. Keller, Georg Thieme Verlag 2 5 Stuttgart, New York).

The preparation of amides, that is to say of compounds of the general formula 1 wherein R3 represents -C-NR6R7, is O effected by reacting activated acid derivatives (e„g» mixed anhydride, acid chloride) with primary or secondary 30 amines of the general formula » 13 - wherein R6 and R7 have the meaning given above.

There may be mentioned as examples of suitable amines: dimethylamine, diethylamine, di-n-propylamine, diiso-5 propylamine, di-n-butylamine, diisobutylamina, di-sec.-butylamine, M~methyl-n-propvlamine, dioctvlamine, dicyclohexylamine, N~*ethylcvclohexylamine, diisopropenyl-amine, benzylamine, aniline, 4-methoxyaniline, 4-di-methylaminoaniline, 3,5-dimethoxyaniline, morpholine, 10 pyrrolidine, piperidine, N-methylpiperazine, N-ethyl-piperazine, M-(2-hvdroxyethyl)-piperazina, M~(hydroxy-iaethyl)-piperazine, 2-(2-hydroxymethyl)-piperidine, 4-( 2-hydroxyethyl)-piperidine, 2-hydroxymethylpiperidine, 4-hydroxymethylpiperidine, 2-hydroxymethvlpyrrolidine, 3-15 hydroxypiperidine, 4-hydroxypiperidine, 3-hydroxypyrro-lidine, 4-piperidone, 3~pyrroline, 2,S-dimethylpiperi-dine, 2,S~dimethylmorpholine„ pyrazoline, imidazoline, oxazolidine, thiazolidine, 2,3-dihydroxypropylamine, N-methy1-2,3-dihydroxypropvlamine, 2-hydroxy-l-(hydroxy-20 methyl)ethylamine, N,N-bis(2-hydroxyethyl)amine, N-methyl-2,3,4,5,6-pentahydroxyhexylamine, S-amino-2,2-dimethyl-l,3-dioxepin-5-ol, 2-hydroxyethylamine, 2-amino-1,3-propanediol, diethanolamine, ethanolamine.

The polyhydroxyalkylamines may advantageously also be 2 5 used in the reaction in protected form, for example in the for® 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 30 2-araino-l-(2,2-dimethyl-l,3-dioxolan-4-yl)-ethanolf the acetonide of l-amino-2,3,4-trihydroxybutane, prepared - 14 - 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 aqueous-5 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/elimination 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 bisalcoholstes [see E. Klingsberg, The Chemistry of Heterocyclic Compounds, 15 Interscience Publishers Hew 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-S47, 20 Marcel Dekker, Mew York, 1969).

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

The synthesis of the starting materials of the general formula I" that are to be alkylated is carried out by 2 5 cyclisation of two reagents, one of which contains the substituent X, that is to say the desired 5- or 6= membered ring of the end product or a precursor for conversion into that ring.

The cyclisation is carried out according to methods Known 30 in the literature (for example Org. Synth. SSL, 86 (1978),, Hacrocyclic Polyether Syntheses, springer VerXag Berlin,, - 15 - Heidelberg, New York 1982, Coord- Chem. Rev. 3,f, 3 (1968), Ann. Chem. 1976 r 916, J. Org. Chem. 110 1984. 1984. id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984" id="p-1984"

[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-, dihromo-, dimesyloxy-, ditosyloxv- or dialkoxycarbonyl-alkylene compounds containing the substituent X and, optionally, from one to five nitrogen 10 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 15 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 20 liquid ammonia, hydrobromic acid and phenol, RedAl(R), lithium aluminium hydride, sodium amalgam, see, for example, Liebigs Ann, Chem. 1977, 1344, Tetrahedron Letters 1976, 3477; the trifluoroacetates are freed, for example, ^ith mineral acids or ammonia in methanol, see, 25 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 CH2COOY), 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 BP Patent Application 232751).

If diesters are used in the cyclisation reaction,, the - 16 - resulting diketo compounds roust 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 5 terminal bisaldehyd.es with the terminal bisajoJLnes 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 61, 1376 (1978) 10 The amines required as starting materials for the cyclisation are prepared analogously to methods known in the literature.

Using an N-protected amino acid as starting material,, reaction with a partially protected diamine (for example 15 according to the carbodiiniide method), removal of the protecting groups and diborane reduction yield a thiamine .

The reaction of a diamine obtainable from amino acids [Eur. J. Med. Chem. - Chim. Ther. 21, 333 (1986)] with 2 0 twice the molar amount of an N-protected o-aaino 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 [seee for example, Inorg. Chem. 25/ 4731 (1986)],, 2 5 In both cases, the number of carbon atoais between the N-atoms can be fixed by the nature of the diamines or amino acids used as coupling partner- The resulting compounds of the general formula 1 wherein V represents a hydrogen atom are complexing agents. They - 17 - can be isolated and purified or can be converted, without being isolated, into metal complexes of the general formula 1 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 therein Y represents a hydrogen 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, nsorpholine, glucamine, N-methyl- and N,N-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 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 - 18 - resulting neutral salts by the addition of water-raiscible solvents, such as, for exaraple, lower alcohols (methanol, ethanol, isopropanol» etc.), lower ketones (acetone, etc.) and polar ethers (tetrahvdrofuran, dioxane, 1,2-5 dimethoxyethane, etc.) and so obtain crystals that can readily be isolated and purified. It has proved especially advantageous to add the desired base to the reaction mixture during the complex formation, thus eliminating one process step. 10 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 assount 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 2 5 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 se, by suspending or dissolving the complex compounds according to the 30 invention in an aqueous nediuas - optionally with the; addition of additives customary in galenic pharmacy -and then optionally sterilising the suspension or - 19 - solution- Suitable additives are, for example, physiologically acceptable buffers (such as, for example, tromethamine), small amounts of complexing agents (such as, for example, diathylenetrianiinepantaacetic acid) or, 5 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 10 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^) , Myr j ) and/or taste-correcting flavourings (for example ethereal 15 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 20 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 2 5 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. 30 The pharmaceutical agents according to the invention preferably contain from 1 jimol 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 5 complexes with the ions of the elements of atomic numbers 21-29, 42, 44 and 57-83; 2. for radiodiagnostics 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 2 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 2 5 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 100-to 1000-tisaes more water-soluble than those for NMR spectroscopy. Furthermore, the agents according to the 30 invention exhibit not only a high stability in vitro but also a surprisingly high stability As 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 - 21 ~ 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 5 0.5 maol/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 10 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. h 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 25 Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York, 1983).

The compounds according to the invention can also be used in radioiaaauno- or radio-therapy. This differs fro® the corresponding diagnostics only in the amount and nature 3 0 of the isotope used. The aim is to destroy tumour cells - 22 - using high-energy short-wave radiation with a minimum range. Suitable B-emitting ions are, for example, 4®Scf 47Sc, 48Sc, 72Ga and 73Ga. Suitable s-emitting ions having short half-lives are, for example, 21~8i, 2x2Bi, 5 2-L3Bi and 214Bi„ with 212Bi being preferred. A suitable photon- and electron-emitting ion is 158Gd, which can be obtained from 1^7Gd by neutron capture.

When the therapeutic agents according to the invention are used in vivo r they may be administered together with 10 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 the cell disorder, the metal ion used and the type of imaging method. 5 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., TIBTEC, October 1986, 262. 2 0 The agents according to the invention are excellently suitable SIS 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 2 5 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 30 according to the invention are administered analogously fco# for example, meglumine diatrizoate in amounts of from - 23 - 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. Bucheler, 5 "Einfiihrung in die Rontgendiagnostik3", G. Thieme, Stuttgart, Mew York (1977).

In summarye 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. 1 5 EXAMPLE 1 a) 3,6,9-tris(p-tolylsulphonyl) -3 ,6,9, IS-tetraasabi-cyclo[9.3.1]pentadeca-l(15),11,13-triene A solution of 35.2 g (200 mol) of 2,6-bis(chloromethyl )-pyridine (dissolved in 700 ml of dimethylformamide) is 20 added dropwise at 100"c, over a period of 3 hours, to 121.9 g (200 mol) of the N,N,,-disodium salt of N,N',NM-tris(p-tolylsulphonvl) -diethylanetriaiaine in 1S00 ml of dimethylformanide. The mixture is stirred overnight at 100 *C* 2 litres of water are added dropwise to the hot 2 5 solution,, and the mixture is allowed to cool to 0"C. The precipitate is filtered off with suction and washed with water. After drying jji 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 30 of a colourless powder. - 24 - 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) ,11,13- 5 triene tetrahvdrosulphate 90.3 g (135 arnol) 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 0*C, and 1.35 litres of absolute 10 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 ijQ vacuo at 50*C. Yields 42.6 g (52.7% of the theoretical yield) of a solid 15 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 ,6,9,15~tetraazahicyclo[9.3.1]pentadeca-l(15),11,13-20 triene 40.0 g (66.8 mmol) of the title compound of Example 1c 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 2 5 and dried over magnesium sulphate. Concentration by evaporation jjq 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 30 found-. C 63.91 H 8.85 N 26.98 - 25 - d) 3,6,9-tris(carboxymethy1)-3,6,9,15-tetraazabicyclo- [9.3.1]pentadeca-l(15),11,13-triene 33.1 g (55.1 !?.m 1) of the title compound of Example ic are adjusted to pH 8.5 in 170 ral of water with 6N 5 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 6N 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 10 kept at 9.5-10 by the addition of SM 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 15 acetone, the solid material is filtered o£fP 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 waterP the ligand is eluted with 0.5M 20 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 ^ater, and then elution is carried out with 0.5N formic acid. Concentration is carried out 2 5 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 30 hygroscopic compound.

Analysis: calc.: C 53.67 H 6.36 N 14.73 O 25.24 found: C 53.55 H 6.43 N 14.65 - 26 - a) Gadolinium cosapiax of 3,6,9-tris(carboxynethyl)- 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca~l(15),11,13-triene 5.0 g (13.14 iomol) of the title compound of Example Id 5 are dissolved in 20 ml of deionised water and added to 2.38 g (6.57 aoaol) of gadolinium oxide. The fixture 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 ] o 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 15 The following relaxivitv in plasma was measured (the relaxation times were measured in a Hinispec p20 (Bruker) at 0.46 tesla (= 20 MHz) at 40*C): -relaxivitv: 7.64 (L/xunol.sec) By way of comparison: 20 dimeglumine salt of the gadolinium complex of diethylene-triaminepentaacetic acid (Gd-DTPA): T^-relaxivitv: 4.95 (L/Mmol.sec) Osmolality of a 0.5 molar solution at 37"c: 0.55 (Osml/Rg water) 2 5 bv way of comparison: dimeglumine salt of Gd—DTPA: 1.1 (Osml/kg water).

In an analogous manner, using iron(III) oxide, Fe203^ the iron(III) complex of 3,6,9-tris(carboxymethyl)-3,6,9,15- tetraazabicyclo[9.3 .1 ]p@ntadeca-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 Si 12.84 Fe 12.81 - 27 - T^-relaxivity (L/sasol»sac) t 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-l(15),11,13-triene 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)-3,6,9,15-tetraazabicvclo[9.3.1]pentadeca-1(15),11,13-triene 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 3,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-l(15),11,13-triene 3.0 g (7.89 nuaol) 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 N-raethylglucaaine solution. Then the product is freeze-dried - Yield: 5.56 g (100% of the theoretical yield) of & ~ 23 » 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 Mn 8.74 5 found: C 45.98 H 5.21 N 11.08 Mn 8.68 EXAMPLE 2 a) 3,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicyclo-[9.3.1]pentadecane 6.0 g (15.77 nrnol) of the title compound of Example Id 10 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 45"C. After 4 hours, the catalyst is filtered off and the filtrate is concentrated by evaporation in vacuo. The residue is purified over 15 ion exchangers as described in Example Id. Crystallisation fron 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 20 found: C 52.94 H 7.89 N 14.37 b) Gadoliniun complex of 3,6,9-tris(carboxymethyl )-3,6,9,15-tetraazabicyclo[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 2 5 of deionised water, and the mixture is stirred for 3 hours at 90"c. The solution is filtered and the filtrate is freeze-dried, yielding 6.5 g (100% of the theoretical yield) of a white, flocculent powder which, according to the analysis, contains 10.3% water. 29 - Analysis: calc.: C 37.76 H 5.03 N 10.36 O 17.76 Gd 29-08 found: C 37.63 H 5.12 M 10.33 Gd 28.97 EXAMPLE 3 5 a) 3,6,9-tris(acetyl)-3,6,9,15~tetraazabicyclo[9.3.1 ]- pentadeca-l(15),11,13-triene 15.8 g (76.6 mmol) of the title compound of Example 1c, 42.7 ml of triethylamine (306.4 mmol) and 50 mg of dimethylaminopyridine (DMAP) are dissolved in 300 ml of 10 absolute methylene chloride. 28.9 ml (306.4 mmol) of acetic anhydride are added, and the mixture 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 15 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 20 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,IS-tatraazabicyclo[9.3.1]™ 2 5 pentadeca~l(15),11,13-triene-15-N-oxide 22.5 g (67.7 miKol) of the title compound of Example 3a ar© 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 0 3.9 ml of 30% hydrogen peroxide solution are added, and the mixture is stirred for a further hour at 70"c. The - 30 - 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 5 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. 10 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-tetraazabicyclo-[9.3.1]pentadeca-l(15),11,13-triene-15~N~oxide 15 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 2 0 ice, and the precipitate is filtered and washed with a large amount of «ater. Drying in vacuo yields an orange powder, which is recrystallised from acetone.

Yield: 9.2 g (48% of the theoretical yield) of yellow rhombuses. 2 5 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* -ethylenedioxy-bis [3,6, S-tris (acetyl) -3,6,9,15-tetraazabicyclo[9.3.1 ]pentadeca-l(15) „ 11, i3-triene-15- 3 0 N-oxide] A freshly prepared solution of ethylene glycol disodium in dimethylformamide (prepared from 620 rag of ethanediol - 31 - and SOO 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 jji 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 15 e) 13,13'-ethylenedioxy-bis[3,6,9~tris(acetyl)-3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-l(15),11,13-triene] 3 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 2 0 hvdrogenated 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 2 5 magnesium sulphate, the solvent is removed in vacuo and the product is crystallised from ether/ethyl acetate. Yield: 2.87 g (87% of the theoretical yield) of whit® flakes.

Analysis: 30 calc.: C 59.81 H 6.97 M 15.50 O 17.71 found: C 59.70 H 6.91 N 15.39 - 32 - f) 13,13'* -athylenedioxy-bis [ 3 ,6,9 , 15-tetraasabicyclo-[9.3.1]pentadeca-1(15),11,l3-triene] 2.5 g (3=46 mmol) of tha 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 jji 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 10 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. 15 Analysis: calc.". C 61.25 H 8.14 H 23.81 O 6.80 found: C 61.17 H 8.20 N 23.93 g) 13,13'-ethylenedioxy-bis[3,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicvclo[9.3.1]pentadeca-l(15),11,13-20 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 6N potassium hydroxide solution. The mixture is 2 5 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 30 from ethanol/acetone yields 1.3 g (57% of the theoretical yield) of the title compound in the form of a very-hygroscopic solid. ~ 33 ~ Analysis: calc» : C 52.80 H 6.16 N 13.69 O 27.25 found: C 52.67 H 6.07 H 13.75 h) Gadolinium complex of 13,13'-etiylenedioxy-bis[3,6, 9-5 tris(carboxymethyl)~3,6,9,lS-tetrsszaiicyclo[9.3.1]- pentadeca-l(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 to 533 mg (1.47 mmol) of gadolinium oxide. The adxture is stirred 10 for 3 hours at 90'c. Tha solution is filtered and the filtrate is freeze-dried.

Yield: 1.85 g (100% of the theoretical yield) of an amorphous powder which, according tn analysis, contains 11.3% water. 15 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 EXMIPLE 4 a) 13-ethynyl-3,6,S-tris(acetyl)-3,£,9,15-terraazabi-20 cyclo[9 . 3 . l]pentadeca-l (15), 11,12-trier.e- 15-N-oxide 10 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 sodina acstylide (18% suspension in xylene/light mineral oil) are added and the 25 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 chronatographed on silica gel (eluant: methanol/acetone = 1:1). Crystallisation from ether/ethyl acetate yields 5.02 g (53% of 30 the theoretical yield) of the title compotmd in the form of a pal® yellow powder. - 34 Analysis: calc.i C 61.27 H 6.49 N 15.05 0 17.19 founds C 61.31 H 6.55 N 14.94 b) 13,13'-(l,3-butadiyne-l,4-diyl)-bis( [3 ,6,9-tris-5 (acetyl)-3,6,9,IS-tetraasafaicyclo [9.3.1jpentadeca- 1(15),11,l3-triene]~15~M-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 10 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 is. vacuo, the residue is chromatographed on silica gel (eluant: 15 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 20 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-tetraazabicvclo[9.3.1]pentadeca-1(15),11,13-triene] 2.5 g (3.37 mmol) of the title compound of Example 4b are 2 5 dissolved in 50 ml of glacial acetic acid and heated to 60 °C. 1.88 g (33.65 iWBOi) 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 30 . 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 in vacuo and - 35 - crystallisation is carried out from ether/acetone.

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

Analysis: 5 calc.: C 64.21 H 6.52 N 15.77 O 13.51 founds C 64.31 H 5.60 N 15.68 d) 13,13'-(1,3-butadiyne-l,4-diyl)-bis[3,6,9,15-tetraaza-bicyclo[9.3.1]pentadeca-l(15),11,13-triene] 1.9 g (2.67 msol) of the title compound of Example 4c are 10 dissolved,, under nitrogen, in 20 ml of dioxane. 2.4 g (21.38 mmol) of potassium tart.-butoxide are added, and the mixture is boiled under reflux overnight. The solvent is rescved in vacuo and the residue is taken up in 20 til of water. The pH is adjusted to 10 with 2N 15 sodius hydroxide solution and the mixture is extracted six times with. 50 nl 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 2 0 yellow oil.

Analysis: calc.: C 63.29 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- 2 5 (carboxymethyl)-3,6,9,IS-tetraasafoicyclo[9.3.1]- pentadeca-1 (15) ,11,13-triene "j 1.0 g (2.18 jmaol) of the title compound of Example 4d is dissolved in 15 nl of water and added, to 1.65 g (17.44 mmol) of chloroacetic acid. The pH is adjusted to 30 9.5 with SH 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 - 35 - potassium hydroxide solution* After acidification with concentrated hydrochloric acid, purification is carried out over ion exchangers as described in Id. Crystallisa1 tion from methanol/acetone yields 1.07 g (61% of the 5 theoretical yield) of a very hygroscopic solid-Analysis: calc.: C 56.57 H 5.75 N 13.89 O 23.73 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-tetraazabi- cyclo[9.3.1]pentadeca-l(15),11,13-triene] 900 lag (1.116 ramol) 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 15 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. 20 Analysis: calc.: C 40.92 H 3.62 N 10.05 0 17.22 Gd 28.20 found: C 40.81 H 3.65 N 10.18 Gd 28.11 EXAMPLE 5 a) 13-chloro-3,6,9-tris(acetyl)-3,6,9,15-tetraazabi-2 5 cyclo[9.3.1]pentadeca-1(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 30 solution. The mixture is extracted three times with 100 ml of chloroform and is dried over magnesium - 37 - sulphate. After removal of the solvent in vacuo, the product is recrysta.ilisad from ether/ethyl acetate.

Yield: S.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 S.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-tetraazabi-cyclo[9.3.1]pentadeca-l(15),11,13-triene 6.0 g (15.67 mmol) of the title compound of Example 5a are dissolved in 300 ml of ethanol. 1 ml of concentrated hydrochloric acid is added, and the mixture is hydrogena-ted 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 ml of 3% sodium carbonate solution ana 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 from ether/ethvl 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) l3-chloro-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene 5.1 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 nosol) of potassium tert. -butoxide are added, and the mixture is boiled under reflux overnight. Working up is carried out as described in Example 4d. - 38 - Yields 3.01 g (90% of the theoretical yield) of a slightly yellowish oil, which crystallises after a short time.

Analysis: 5 calc.: C 54,88 H 7.12 N 23.28 Cl 14-73 found: C 54.93 H 7.06 N 23.41 Cl 14-81 d) 13-chloro-3,6 , 9-tris (carboxymethyl) -3,6,9,15-tetra-a2abicyclo[9.3.1]pentadeca-l(15),11,13-triene 2.38 g (11.65 mmol) of the title compound of Example 5c 10 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 6N potassium hydroxide 15 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: 20 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 f 9,15-tetraazabicyclo[9.3.1]pentadeca-1(15), 11,13-triene 2 5 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 ismol) of gadolinium oxide. The raixture is stirred for 3 hours at 90"C. The solution is filtered and the filtrate is freeze-dried. 30 Yields 4.9 g (100% of the theoretical yield) of a white amorphous powder which, according to the analysis,, contains 11.9% water. - 39 - Analysis: calc.: C 35,88 H 3.54 N 9.85 O 16.87 Cl 6.23 Gd 27.63 founds C 35.94 H 3.57 N 10.01 Cl 6.17 Gd 27.56 T^-relaxivity (L/mmol.sac), 40°C, water, 20 MHz: 5.44. 5 EXAMPLE S a) 3,6,9,15-tetraa2abicyclo[9.3.l]pentadeca-l(15),11,13-triene-15-N-oxide 4.5 g (12.9 mmol) of tha title compound of Example 3b are dissolved,, under nitrogen, in 40 ml of dioxane. 5.8 g 10 (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. 15 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(carboxymethyl)-3,6,9,15-tetraazabicyclo-[9.3.1]pentadeca-l(15),11,13-triene-15-N-oxide 20 2.4 g (10.7/ 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 25 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: 30 calc.: C 51.51 H 6.10 N 14.14 O 28.26 found: C SI.63 H 6.01 N 14.08 - 40 ~ c) Gadolinium complex of 3,6,9-tris(carboxynethy1)- 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),11,13-triene-15-H-oxide 2.1 g (5.3 nuaol) of the title compound of Exaaple 6b are 5 dissolved in 15 ml of deionised water and added to S35 mg (2.65 mmol) of gadolinium oxide. The mixture is stirred for 3 hours at 90"C. The solution is filtered and the filtrate is freeze-dried* Yields 3.2 g (100% of the theoretical yield) of an ■0 amorphous ponder which, according to the analysis, contains 10.7% water.

Analysis: calc-: C 37.08 H 3.84 N 10.18 0 20.34 G<5 28.56 found: C 37.18 H 3.79 N 10.21 Gd. 28.48 15 EXAMPLE 7 a) 3,6,9-tris(p-tolylsulphonyl)-3,6,9-triaza-14-oxabi- cvclo[9.2.l]tetradeca-1(13),11-diene h solution of 33 g (200 mmol) of 2,5-bis (ciloromethyl) -furan in 700 ml of dimethylformamide is added dropwise at 20 100"C, over a period of 3 hours, to 121.9 g (200 suaol) of the N,Nw-disodium salt of N,N' ,N"-tris(p-tolylsulphonyl)-diethylenetriamine in 1600 ml of dimethylfor~aaiaide. Hie mixture is stirred overnight at 100"c. 2 litres of water are added dropwise to the hot solution. The mixture is 2 5 cooled to 0* C« 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: 30 calc.: C 56.60 H 5.36 N 6.39 O 17.03 S 14.62 found: C 56-52 H 5.42 N 6.30 S 14.60 ~ 41 « b) 3,6,9-triaza-14-oxabicyclo[9.2.1]tetradeca-1(13),11-diens 30 g (45.61 mmol) of the title compound of Example 7a are suspended in 500 ml of liquid ammonia at -40°C. Then 5 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 10 100 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 15 on silica gel (eluant: acetonitrile/water/32% ammonia solution = 10:3:1).

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

Analysis: 20 calc.I 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(ethoxycarbonylmethvl)~3,6,9-triaza-14-oxabicyclo [9.2.1]tetradeca-1(13),11-diene 7 ml (62.5 mmol) of bromoacetic acid ethyl ester are 2 5 slowly added dropwise at 5QeGf 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 romol) of anhydrous sodium carbonate in 150 ml of dimethylformamide. The mixture is stirred for 4 hours at 50"C. The 30 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 3,619-tris (carboxymethyl) - 3,6,9-triaza-14-oxcibicyclo[9 . 2 .1 ] tetradeca-1 (13), 11-diene 5.0 g (11.02 imaol) of the title compound of Example /c are dissolved in 80 nl 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 to 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 colium (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% water.

Analysis: C 36.70 H 3.85 N 8.03 0 21.39 Gd 30.03 C 36.51 H 3.81 N 8.11 Gd 29.91 - 43 - EXAMPLE S Gadolinium complex of 3,6,9-tris(carboxymethyl)-3,6,9,14-tetraazabicyclo[9.2.1]tetradeca-1(13), li-diene 10.0 g (22.04 amiol) of the title compound of Example 7c 5 are dissolved in 150 si 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 by evaporation- The residue is transferred to a shaking autoclave, and 3.54 g 10 (66.12 mmol) of ammonium, chloride are added. After the addition of vanadium oxide catalyst (US Patent 2 478 456, Chem. AJbstr. M., 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 15 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 2 0 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 2 5 mixture is stirred for a further hour 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 elusts is freeze-dried. 30 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- 44 Analysis: calc.: C 36.84 H 3.87 N 10.74 O 18.40 Gd 30.15 found: C 36.75 H 3.91 N 10.68 Gd 30.04 EXAMPLE 9 5 a) 15-methoxy~3, 6 ,9~tris (p-tolylsulphonyl )~3t, 6 £, 9-triaaa-bicyclo[9.3 .1 ]pant.adeca-l(15), 11, 13-triene 182.85 g (300 mmol) of the N,N"-disodium salt of N,N',N"-tris(p-tolylsulphonyl)diethylenetriamine are dissolved in 2.4 litres of dimethylformamide and heated to 100*C. A '0 solution of 88.2 g (300 mmol) of 2,6-bis (broraomethyl) ~ 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 0~C. 15 The precipitate is washed with a large amount of water and dried in vacuo (60"c). Crystallisation fro® aceto-nitrile yields 119.3 g (57% of the theoretical yield) of the title compound in the form of a slightly cream-coloured powder. 20 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[9.3.1]pentadeca-1(15),11,13-triene 25 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 Sa in 2 litres of dibutyl ether» and the mixture is heated under reflux overnight. The mixture is cooled in an ice-bath and excess lithium 30 aluminium hydride is destroyed with ethanol aswi then with water. The mixture is concentrated to dryness by ~ 45 ~ evaporation, and the residue is taken up in one litre of 2N 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 5 residue is chromatographed over silica gal (eluant: methanol/32% aqueous ammonia solution = 10:1).

Yield: 8»56 g (27% of the theoretical yield) of a yellowish oil.

Analysis: 10 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-hydroxy-3,6,9-tris(tert.-butoxvcarbonylmethyl)- 3,6,9-triazabicyclo[9.3.1]pentadeca~l(15),11,13-triene 8.3 g (37.50 mmol) of the title compound of Example 9b 15 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. 20 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 2 5 remains is chromatographed on silica gel (eluant: methylene chloride/methanol = 15:1).

Yield: 13.32 g (53% of the theoretical yield) of the title compound in the form of a colourless oil.

Analysis: 30 calc.: C 63.91 H 8.76 N 7.45 0 19.87 found: C 63.83 H 8.85 N 7.49 - 46 - d) 15-hydroxy-3,6,9-tris (carboxymethyl)-3 ,6, S-triazabi-cyclof 9.3.1]pentadeca-l(15),11, 13-triene 13.0 g (23.06 mmol) of the title compound of Example 9c are dissolved in 150 ml of trifluoroacetic acid and 5 stirred, overnight at room temperature. The mixture is concentrated jja 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 10 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 founds C 54.51 H 6.30 N 10.57 15 e) Gadolinium complex of 15-hydroxy-3,6,9-tris(carboxymethyl )-3,6,9~tria2abicyclo[9.3.1]pentadeca-1(15),11,13-triene 4.0 g (10.1 mmol) of the title compound, of Example 9d are dissolved in 25 ml of deionised ^ater and added to 20 1.84 g (5.05 xsmol) of gadolinium oxide. The mixture is stirred for 3 hours at 90'C, l 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 25 theoretical yield) of an amorphous powder which, according to the analysis, contains 13.5% water.

Analysis: calc.: C 39.33 H 4.04 N 7.65 0 20.38 Gd 2^ ,61 found: C 39.41 E 4.10 N 7.58 Gd 28.51 / EX&HPLS 10 a) 6-benzyl~3,9-bis(p-tolylsulphonyl)-3,6,9,15-tetraaza-bicyclo[9.3.1]pentadeca-l(15),11,13-triene A solution of 35.2 g (200 mmol) of 2,6~bis(chloro-5 methyl)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,N"-bis (p-tolylsulphonyl) -N41 -benzyldiethylenetri-amine in 1500 ml of dimethylformamide. The mixture is 10 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 15 yield) of a cream-coloured powder.

Analysis: calc.: C 63.55 H 6.00 N 9.26 0 10.58 S 10.60 founds C 63.48 H 5.94 M 9.18 S 10.63 b) 6-benzyl~3,6,9,l5-tetraazabicyclo[9.3.1]penfcadeca-20 1(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 dibutyl ether, and the mixture is heated under reflux overnight. After cooling 2 5 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 pK 11 with 6N potassium hydroxide solution. ■ Extraction is carried out 30 six times with 100 ml of chloroform, .followed by drying over magnesium sulphate and concentration jja vacuo. Chromatography on silica gel (eluant: ethanol/32% - 48 aqueous ammonia solution - 12:1) yields 22.4 g (61% of the theoretical yield) of a yellowish oil, which solidifies to a transparent solid.

Analysis: 5 calc.: C 72.94 H 8.16 N 18.90 found: C 72.75 H 8.23 N 18-81 c) 5-henzyl-3,9-bis(ethoxycarbonyImethyl)-3„6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene 10 g (33.74 mmol) of the title compound of Example 10b 10 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 over-15 night 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 = 20 10:1).

Yield: 13.12 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 N 11.96 O 13.66 2 5 found: C 66.51 H 7.81 N 11.88 d) 3,9-bis(carboxymethyl)~3,6,9,15~tetraazabicyclo~ [9.3.1]pentadeca-l(15),11,13-triene 12 g (25.S mmol) of the title compound of Example 10c are dissolved in 100 ml of ethanol and heated to 60C« 32 ml 30 of 2N sodium hydroxide solution are added dropwise to that solution, and the Mixture is boiled under reflux for one hour- The mixture is concentrated to dryness by - 4S - 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. 5 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: 10 calc,: C 55.88 H 6.88 N 17.38 O 19.85 found: C 55.79 H 6.94 H 17.27 e) Manganese(II) complex of 3„9-bis(carboxymethyl)- 3,6,9,15-tetraa2abicyclof 9.3.1:pentadeca-1(15),11,13-triene 15 4 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 coluurn (IR-120) and then 20 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. 2 5 Analysis: calc.I 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) 3f6—bis(p-tolylsulphonyl)-3,6,12-triasabicyclo™ 30 [6.3.1]dodeca-l(12),8,10-triene A solution of 35.2 g (0.2 xsol) of 2,6-bis (chl or ©methyl) - - 50 - pyridine (dissolved in 700 ml of dimethy 1 formamide) 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(p- tolylsulphonyDethylenediamine in 1600 ml of dimethyl-5 formamide. The mixture is stirred overnight at 110°C. 2 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 in vacuo (60*C), the product is recrystallised from aceto-10 nitrile.

Yields 67.9 g (72% of the theoretical yield) of a cream-coloured powder.

Analysis: calc.: C 58.58 H 5.34 N 8.91 O 13.57 S 13.60 15 found: C 58.41 H 5.37 N 8.85 S 13.53 b) 3,6,12-triazabicyclo[6.3.1]dodeca-l(12),8,10-triene trihydrosulphate 67.0 g (142 nunol) of the title compound of Example 11a are introduced into 200 ml of concentrated sulphuric 2 0 acid and stirred for 48 hours at 100"C. The mixture is cooled to 08C 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 2 5 evaporation. Drying in vacuo (60°C) 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 30 found: C 23.57 H 4.24 N 9.11 S 20.96 c) 3#6P12-triasabicyclo[6.3.l]dodeca-l(12), 8,10-triene 42.0 g (91.3 mmol) of the title compound of Example lib - 51 - 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 5 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 H 8.03 N 25.74 10 founds C 66.17 H 8.09 N 25.67 d) 3 ,6-bis (carboxymethyl) -3 , 6,12-triazabicyclo [6.3.1]-dodeca-1(12),8,10-triene 10 g (61.27 mmol) of the title compound of Example 11c are dissolved in 100 ml of water and added to 17.37 g 15 (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 6M potassium 20 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. 2 5 Analysis: calc.: C 55.90 H 6.14 N 15.05 O 22.92 found: C 55.81 H 6.19 N 14.94 e) Manganese complex of 3,6-bis(carboxymethyl)-3,6,12-triasabicyclo[S.3.1]dodeca-l(12) ,8,10-triene 30 10.0 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 - 52 - mixture is stirred for 2 hours st 80" C. 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 80"c. The mixture is filtered and the 5 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; 10 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-15 [9.3.1]pentadeca-l(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 ramol) of the mono-hydrate of the calcium trisodium salt of DTPA, CaNa3DTPA, 20 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.

SXAHPLE 13 2 5 Preparation of a solution of the meglumine salt of the manganese(II) complex of 3,6,9-tris(carboxymethyl)- 3,6,9,15-tetraasahicvclo[9.3.1 ]pentadeca~l(15), 11 „ 13-triene 34.92 g (50 mmol) of the compound described in Example lh 3 0 (water content 12,29%) are dissolved in 65 ml of water - 53 - (p.i.). After the addition of 492 sag (1 mmol) of the monohydrate of the calcium trisodium salt of DTPA, CaNa3DTPA, the solution is made up to 100 ml with water p „ i. . The solution is then ultrafiltered, trans-5 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: jo 4.000 g of the gadolinium complex described in Example le 3.895 g of mannitol 0.100 g of polvoxvethylene-polyoxypropylene polymer 0.005 or of flavourings 8.000 g 1 5 EXAMPLE 15 Preparation of a solution of the indium-Ill complex of 3,6,9-tris(carboxymethyl)-3,6,9,IS-tetraazabicvclo-[9.3.1]pentadecane A solution of 5 ml of indium-Ill chloride in 1 ml of N 20 hydrochloric acid is added to a solution of 100 &g of the compound described in Example 2a in 5 ml of a mixture of a 150 mmolar sodium chloride solution and a 150 xasxolar sodium acetate solution (pH 5.8). The pH is adjusted to 7.2 by the addition of 0.111 sodium hydroxide solution, 25 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 - 54 - analogous manner using vttriuxa-90 chloride.

EXAMPLE 16 a) 3,6,9-tris(p-tolylsulphonyl)-14-oxa-3,6,9-triazabi-cyclo [9.2.1 ] tetradecane 5 39.01 g (64 mmol) of the N,N"~disodium salt of N,N',Nr- tris(p-tolylsulphonyl)diethylenetriamine dissolved in 210 ml of dimethylformamide are added dropwise at 100"c, over a period of 2 hours, to a solution of 28.19 g (64 raraol) of 2,5~bis(p-tosyloxyraethyl)tetrahydrofuran in 10 500 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 0*C. The precipitate is filtered off with suction, cashed with water and dried ml vacuo at 50°. Recrystallisation from 15 acetone yields 33.5 g of the title compound in the form of a white powder, melting point 175-178"C.

Analysis: calc.: C 56.26 H 5.94 N 6.35 S 14.53 found: C 56.01 H 5.99 N 6.28 S 14.29 20 b) i4-oxa-3,6,9-triazabicyclo[9.2.1]tetradecane 30 g (45.3 mmol) of the title compound of Example 16a are introduced into 90 ml of concentrated sulphuric acid and stirred for 24 hours at 90"C. The mixture is then, cooled to 0"CP and 350 ml of dry ether are added drop-2 5 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 30 evaporation in vacuo„ yielding 6.23 g (69% of the theoretical yield) of the title compound in the form of a - 55 - white powder. Analysis: calc.: C 60.2/ foundt C 60.03 H 10.62 N 21.08 H 10.75 N 20.95 5 c) 3,6,9-tris(carboxymethyl)-14-oxa-3,6,9-triazabicyclo- [9.2.1]tetradecane 6 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 10 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 15 acid is added slowly until the pH reaches 2, and the mixture is concentrated by evaporation in vacuo. The residue is dissolved in 100 ml 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. 20 Then the desired substance is eluted with 0.5M 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 2 5 then slution 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). 3 q Analysis: calcC 51.47 H 7.29 N 11.25 found: C 51.60 H 7.21 N 11.38' - 56 - d) Gadolinium complex of 3,6,9-tris(carboxymethyl)-14-oxa-3 ,6,9~tria2abicycio[ 9.2.1 ] tetradecane 3.73 g (10 mmol) of the title compound of Example 16c are dissolved in 15 ml cf water and stirred for 3 hours 5 with 1.81 g (5 mmol) of gadolinium oxide at 80"C. The resulting solution is filtered and is precipitated by stirring with,, in succession,, 0.5 g of cation exchanger (1R 120) and 0.5 g of anion exchanger (IRA 67); the solution is filtered again and is subjected to freeze-10 drying, 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 M 7.96 Gd 29.80 15 found: C 36.30 H 4.61 N 7.82 Gd 29.59 (water content taken into account) EXAMPLE 17 a) 3,6,9-tris(p-tolylsulphonyl)-14-thia-3,6,9-triazabi-cyclo[9.2.1]tetradeca-1(13),11-diene 2o 60.97 g (100 mmol) cf tie N/N"-disodium salt of N,N',N"-tris(p-tolylsulphonyl)diethylenetriamine are dissolved in 800 ml of dimethylfcrmazdde, and 19.9 g (110 mmol) of 2,S-bischloroinethyltiiiophene dissolved in 3 30 ml of dimethylformamide are added dropwise at 50 °C over a 2 5 period of 90 minutes. The mixture is stirred for a further 90 minutes at 50"C, 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 30 is r©crystallised fros dioxane. 47.1 g (70% of the theoretical yield) of tiie title compound are obtained in the form, of a light-yellow powder, melting point - 57 - 265-268°C.

Analysis: calc.: C 55.25 H 5.24 N 6.24 S 19.03 found: C 55.38 H 5.44 N 6.10 S 19.01 5 b) 14~thia-3,6,9-triazabicyclo[9.2.1]tetradeca-1(13),11-diene 45 g (66.8 rasnol) of the title compound of Example 17a are introduced into 130 ml of concentrated sulphuric acid and stirred for 24 hours at 90-95"C. After cooling 10 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 dichloro-methane each time, is dried over magnesium sulphate and 15 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: 20 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(carboxymethyl)-14~thia-3,6,9-triasabi-cyclo[ 9.2. l ] tetradeca-1 (13) , 11-diene 7.5 g (35.5 mmol) of the title compound of Example 17b 2 5 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 45-50"C and the pH value is kept at 9.5-10 during' that time by the addition 3 0 of further potassium hydroxide solution» After cooling to 10*C, concentrated hydrochloric acid is added until •Che pH reaches 2. The precipitate that forms is isolated - 58 - by suction filtration and is dissolved in 100 ml of water ? tha solution is adsorbed on a cation exchange column (IR 120) and the column is washed with 2 litres of water and than with 0.5N ammonia solution. The ammonia fraction is concentrated by evaporation jln, vacuo, the residue is dissolved in 100 ml of water, and the solution is bound to an anion exchanger (IRA 57). The exchanger column is eluted with water and 0.5M formic acid» The title compound is obtained from the acid fraction by concentration by evaporation la vacuo. For further purification, the compound is dissolved in methanol, and acetone is added until a precipitate forms. The mixture is cooled to 0'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 d) Gadolinium complex of 3,6,9-tris(carboxymethyl)-14-thia-3,6 ,9-tria2abicyclo[ 9.2.1 ] tetradeca-1 (13), 11-diene 2 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%. „ 59 - 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) 5 EXAMPLE IS a) 13-methoxy-3 ,6 , 9-tris (p-tolylsulphonyl) -3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1 (15),11,13-triene 60.97 g (100 mmol) of the M,N5!-disodium salt of N#N',N"-tris(p-tolylsulphonyl)diethylenetriamine are dissolved in 10 800 ml of dimethylformamide, and 47.76 g (100 rmaol) of 2 ,6-bis (p-tolylsulphonvloxymethyl) -4-methoxypvridine 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 15 of water are added dropwise; the precipitate that forms is filtered off with suction and is washed with water, and tha product is dried in a vacuum drying cabinet and recrystallised from isopropvl alcohol, yielding 43.3 g (62% of the theoretical yield) of the title compound in 2 0 the form of a white powder.

Analysis: calc.: C 56.71 H 5.48 N 8.015 S 13.76 found: C 56.90 H 5.31 N 8.00 S 13.59 b) 13-methoxy-3,6,9,15-tatraasabicvclo[9.3 -1]pentadeca~ 2 5 1(15),11,13-triene 30 g (42.9 mmol) of the title compound of Example 18a are stirred for 24 hours at 95"c with 100 ml of concentrated sulphuric acid. After cooling to 0*C, 400 ml of ether are added dropwise and the precipitate that forms 30 is filtered off with suction and dissolved in 60 ml of 40% sodium hydroxide solution- The solution is extracted — so — five times with 75 ml of dichloromethane each time, is dried over magnesium sulphate and is concentrated by evaporation in vacuo. The residue is recrvstallised from diisopropyl ether, yielding 6.59 g (65% of the theoreti-5 cal 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 10 c) 13-raethoxv-3,6,9-tris(carboxymethyl)-3,6,9,15-tetra-a2a.bicyclo[ 9.3 .1 ]pentadeca-1 (15 ) ,11,13-triene 6.2 g (26.2 mmol) of the title compound of Example 18b are dissolved in 40 ml of tjater, and 9.90 g (104.8 raiaol) of chloroacetic acid are added. The pH value is adjusted 15 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 20 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 2 5 with a large amount of water and then with 0.5N ammonia solution. The basic eluate is collected and concentrated toy 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 30 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 - 61 ~ 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 5 d) Gadolinium complex of l3-methoxy-3,6,9-tris(carboxymethyl )-3,6,9,15-tetraazabicyclo[9.3.1]pentadeea-1(15) ,11,13-triene 5 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) 10 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: 15 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 )-20 3,6,9,l5-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13- triene 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 miaol) of sodium carbon-25 ate in. 200 ml of acetonitrils, and the mixture is stirred for 24 hours at room temperature.

The mixture is concentrated by evaporation jji vacuo and the residue is taken up in 300 ml of water and is extracted three times with 200 ml of methylene chloride. 30 After drying the organic phases over magnesium sulphate, — 62 — concentration is carried out i& vacuo and the oil that remains is chromatographed on silica gel (eluant: methylene chlorida/ethanol = 15:1).

Yield: 14.08 g (83% of the theoretical yield) of a 5 colourless oil* Analysis: calc.: C 59.73 H 8.12 N 9.61 O 16.46 Cl 6.08 found: C 55.67 H 8.25 N 9.58 Cl 6.01 b) 13-(^-pyrrolidine)-3,6,9~tris(tert.-butoxvearbony1-10 methyl)-3,6,9,15-tetraasabicyclo[9.3.1]pentadeca- 1(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 boroI) of the title compound of Example 19a, 3.94 g (46.3 mmol) 15 of pyrrolidinone and 612 mg (2.32 msnol) of 18-crown-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 20 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). 25 Yield: 5.7 g (39% of the theoretical yield) of a colour-lass 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 - 63 - c) 13-(N~pyrrolidino)-3,6#9-tris(carboxynetHyl) -3,6,9,l5-tatraasabicyclo[9.3.1]pentadeca-1(15),11,13 triene 5.1 g (8.07 mmol) of the title compound of Example 19b are dissolved in 50 ml of trifluoroacetic acid and stirred for 6 hours at room temperature. file solvent i removed .la 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 tha 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 13-(M~pyrrolidi.no)-3 ,S ,9-tris(carboxymethyl)-3,6,9,15-tetraa2abicyclc*3.3.1]-pentadeca-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 wig (2.7 mmol) of gadolinium oxide. The fixture is stirred for 3 hours at 90'C. The solution is filtered and the filtrate is freeze-dried„ Yields 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 N 11.34 0 18.13 Gc 25.46 found: C 40.74 H 4.37 N 11.28 Gd 25.41 - 64 - EXAMPLE 20 a) 13—aside—3 ,6,9-tris (tert. -butoxycarbonylmethyl) - 3,6,S,15-tetraa2abicyclo[9.3.1] pentadeca-1(15)„11,13-triene 5 21 g (36.01 xaiaol) 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 ag (3-6 mmol) of 18-crosn-6 are added. The mixture is stirred for 48 hours at 90 ° C. 10 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 chromato-15 graphed on silica gel (eluants methylene chloride/ethanol = 15:1) .

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

Analysis: 20 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. -butoxycar bony Ime thy 1) - 3,6,9,15-tetraazabicyclo[9.3.1 ]pentadeca-1 (15) ,11,13- triene 25 10 g (16.96 mmol) of the title compound of Example 20a are dissolved in 400 ml of ethanol and added to 1 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 3 0 filtrate is concentrated by evaporation in vacuo. The oil that remains is chromatographed on silica gel - 65 (eluant: methylene cliloride/raethanol/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 f 9 ,15-tetraaza bicyclo[9.3.1]pentadeca-1(15),11,13-triene 8.2 g (14.55 mruol) 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 jjj 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]pentadeca-1(15),11,13-triene 4.8 g (12.14 vmol) of the title compound of Example 20c are dissolved in 35 nl of deionised water and added to 2»2 g (S.07 snol) of gadolinium oxide. The mixture is stirred for 3 hours at 90"C and the pH value is kept at 5.5 by the addition of acetic acid. The solution is filtered and passed over a column filled with poly(4-vinylpyridine). After treatment with activated carbon, the mixture is filtered again and is freeze-dried. Yield: 6.07 g (91% of the theoretical yield) of an - 66 - amorphous powder which, contains 12.1% water.

Analysis: calc.; C 37.15 H 4.06 found; C 37.08 H 4.17 2XAHPLE 21 a) 13-(hydroxyacetamido )-3,6,9~tris( tert. -butoxycarbonyl-methyl) -3, S, 9,15-tetraazabicyclo [9.3.1 ]pentadeca-1(15),11,13-triene 5.8 g (10.28 ramol) of the title compound of Example 20b, 861 mg (11.32 mmol) of glvcolic acid and 1.53 g (11.32 msaol) 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 dicyclohexylcarbo-diimide 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-(hydroryacetamido)-3 ,6 , 9-tris (carboxymethyl)- 3 „ 6 f 9,15-tetraazabicyclo[ 9.3.1 ]pentadeca-1 (15) „ 11,13-triene 2.7 g (4.34 mmol) of the title compound of Example 21a according to the analysis, N 12.74 O 17.47 Gd 28.61 N 12 . 68 Gd 28.54 - 67 - are dissolved in 40 wl of trifluoroacetic acid and stirred for 6 hours at rooxa temperature. The mixture is concentrated by evaporation jji vacuo and the residue is purified over an anion exchanger as described in 5 Example Id.

Crystallisation from isopropanol yields 1„55 g (79% of the theoretical yield) of a white powder.

Analysis: calc.: C 50.32 H 6.00 N 15.45 O 28.23 10 found: C 50,24 H 6.07 N 15-49 c) Gadolinium complex of 13~(hydroxyacetamido)-3,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicyclo-[9.3.1]pentadeca-1(15),11,13-triene 1.45 g (3.2 mmol) of the title compound of Example 21b 15 are dissolved in 10 ml of deionised water and added to 580 mg (1.6 sxiaol) of gadolinium oxide. The mixture is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freese-driad.

Yield: 1.94 g (100% of the theoretical yield) of an 20 amorphous ponder 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 2 5 EXAMPLE 22 a) 13-chloro-3,6,9-tris(p-tolylsulphonyl)-3,6,9-triaza- bicyclof 9.3.1]pentadeca-1(15),11,13-triene 182.85 g (300 mmol) of the N,Nw-disodium salt of N,N",N"~ tris(p-tolylsulphonyl)diethylenetriamine are dissolved in 30 2.4 litres of dimethylformamide and heated to 100*C. A - 68 - solution of 63.15 g (300 nunol) of 4~chloro~2,6-bis-(chloromethyl)pyridine in one litre of dimethylformasaide is added dropwise over a period of 3 hours. The mixture is stirred overnight at 100°C. 5 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"c). Crystallisation froio. ace tor* i tr i 1 e yields 128.7 g (61% of the 10 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 b) 13-(N-morpho1ino)-3,6,9-tris(p-tolylsulphonyl)-3 ,6,9-triasabicyclo[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 20 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 50°Cf the product is r©crystalUsed from acetone, yielding 87.72 g (65% of the theoretical 2 5 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-tetraazabicyclo-30 [9.3.1]pentadeca-1(15),11,13-triene 86 g (114 mmol) of the title compound of Example 22b are - 69 - 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 5 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 theoreti-10 cal yield) of a yellowish oil,, which crystallises alien 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 15 d) 13- (M-morpho 1 ino) -3 ,6 „ 9-tris (carboxymethyl) -3 ,6,9 ,15-tetraazabicyclo [ 9 .3.1]pentadeca-1 (15) f11,13-triene 10 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 20 9-5 with 6M 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 2 5 exchangers as described in Example id. Crystallisation from msthanol/acetone yields 9.9 g (62% of the •theoretical yield) of the title compound in the form of a very hygroscopic solid.

Analysis: 30 calc,: C 54.18 H 6.71 M 15.05 0 24.06 found: C 54.09 H 6.82 N 15.01 - 70 - e) Gadolinium complex of 13-(M-iaorpholino)~3 ,6,9-tris-(carboxymethyl)~3,6,9,15-tetraazabicyclo[9.3.1] pentadeca-1 (15) ,11,13-triene 9 g (19.33 mmol) of the title compound of Example 22d 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 90"c and the pH value is kept at 5.5 by the addition of acetic acid. The solution is filtered and passed over a column filled with poly(4-10 vinvlpyridine). 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. 15 Analysis: calc.-. C 40.70 H 4.55 N 11.30 0 18.07 Gd 25.37 found; C 40.63 H 4.64 M 11.25 Gd 25.28 EXAMPLE 23 a) 13-chloro-3,6,9-tris(benzyl)-3,6,9,15-tetraazabi-2 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 dimethylforxaaiaide and heated to 70"C. 26.43 g (154.5 mmol) of benzyl bromide are added 25 dropwise over & period of 30 minutes, and the mixture is stirred for 24 hours at 70*c.

The solvent is removed in vacuo and the residue is taken up in 250 ml of 3N sodium hydroxide solution. The mixture is extracted five times with 150 ml of methylene 30 chloride and the organic phases are dried over magnesium sulphate. After concentration by evaporation in, vacuo „ - 71 the residue is chromatographed on silica gel (eluant: isopropanol/triethvlamine = 20:1).

Yield: 17.97 g (91% of the theoretical yield) of a pale yellow oil. 5 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 b) 13-carboxv-3 ,6,9-tris(benzyl)-3,6,9,15-tetraazabi-cyclo[9.3.1]pentadeca-1(15),11,13-triene 10 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 1,2-15 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 2 5 again by evaporation, and the residue is chromatographed on silica gel (eluant: chloroform/methanol/triethylamine = 20:15:1).

Yield: 5.16 g (29% of the theoretical yield) of a pale yellow solid. 30 Analysis: calc.: C 76.27 H 6.79 N 10.78 0 6.16 found: C 76.19 H S.88 N 10.71 - 72 - c) 13-(morpholinocarbonyl )-3 , S, 9-tris(benzyl)-3 5 r 9,15-tatraa2abicyclo[9.3.1]pentadeca-1 (15) ,11,13-triene 5.0 g (9.62 mmol) of the title compound of Example 23b, 922 mq (10.58 mmol) of morpholine and 1.43 g (10»58 mmol) 5 of l-hydroxy-lH-benzotriazole hydrate are dissolved in 10 ml of absolute dime thy 1 f orra&mide and cooled to 0"C. 2.18 g (10.58 mmol) of dicyclotxexylcarbodiiniide are added, and the Mixture is stirred for one hour at 0*C and then overnight at room temperature. 10 The solution is poured into 180 nl of ice-water and extracted three times with 150 toil 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/triethvlamine = 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 20 found: C 75.37 H 7.27 N 11.83 d) 13-(morpholinocarbonyl)-3,6,9,15-tetraazabicyclo-[9.3.1]pentadeca-1(15),11,13-triene 4.1 g (6.96 mmol) of the title compound of Example 23c are dissolved in 250 ml of ethanol and added to 0.5 g of 25 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 . 3 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 founds C 60.08 H 7.97 N 21.81 e) 13-(morpholinocarbonyl)'-3,6,9-tris(carboxymethyl)-3,6,9,15~tstraa2eJhicyclo[ 9.3.1]pentadeca-1 (15), 11,13-triene 1.6 g (5.0 mmol) of the title compound of Example 23d are dissolved in 25 sal of water and added to 1.89 g (20 mmol) of chloroacetic acid. The pH is adjusted to 9.5 with 6M 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.

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 O 25.94 founds C 53.41 K 6.47 N 14.08 f) Gadolinium complex of 13-(morpholinocarbonyl)-3 ,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicyclo- [9=3.1]pentadeca-1(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 fixture is stirred, for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried.

Yield: 1.9/ g (100% of the theoretical yield.) of a white amorphous powder which,, according to the analysisf 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 - 75 - Example for in vivo NHR diagnostics: Following the recording of a pre-image using a nuclear spin tomograph (manufacturer: General Electric, 2 tesla), 0„l mmol of the gadolinium complex of 3,6,9-tris(carboxy-5 methyl)-3,6,S,l5-tetraa2abicyclo[9.3.1]pentadeca- 1(15),11,13-triene [Example le] per kg was administered, i.v. into a caudal vein of a nalced female Balb/c nu/nu mouse weighing 20 g and having a subcutaneous HT 29 colon carcinoma. The substance was dissolved in bi-10 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 l, 23 and 43 minutes after administration of the contrast agent in the region of the liver and of the tumour. 15 It was possible to demonstrate that the signal intensity in the tumour rose and did not fall again over the period observed. 76 - The figure shows a transverse section of a naked Balb/c nu/nu mouse having an HT 29 colon careinotaa before and after the i.v. administration of the contrast agent. The images were recorded in tha 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= Macrocyclic compounds of tha general formula I Z-N (I)

1. A / wherein .... represents a single bond or a double bond, q represents the numbers 0 to 5,

2. 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=0, =MR2, -CHR3- or =CR3-, E represents a nitrogen atom, a sulphur atom, an oxygen atom, the group =M (, =c- or >MR4, A(-) OH, F represents (-CHR3 -) n or (=CR8) n, R1 represents a hydrogen atom or a halogen atom or a C^-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, R2 represents a hydrogen atom or a C^-Cg-alkyl group, R3 represents a hydrogen atom or a halogen atom, a phenyl group or a CX-C6 -alkyl group optionally substituted, by one or mora phenyl and/or hydroxy groups, or represents the radical OR5, tha substituent ~(C)iNRsR7 or ~ 78 ~ hydroxylated or carboxylatad. -alkyl group, R5 represents a C^-Cg-alkyl radical optionally substituted by from 1 to 3 hydroxy groups, R6 and R7, independently of each other, represent 5 hydrogen atoms, the radical R^, or phenyl or benzyl radicals optionally substituted by from 1 to 3 hydroxy groups, or R5 and R7, together with the nitrogen atom, for® a saturated or unsaturated 5- or S-mes&bered ring that optionally contains a further nitrogen, oxygen or 10 sulphur atom or a carbonyl group and that is optio nally substituted by from 1 to 3 radicals R5, or one of the substituents R6 and R7 represents the radical 0 -OR5, R8 represents R1 or G, 15 1 represents the number 0 or 1, n represents the number 0 or 1, G represents a second raacrocycle of the general formula II that is bonded via a direct bond, a bis(carbonvlamino) group (-NH-CO-CO-NH-) or via a 20 C1-C2o~alkylans group that optionally carries carbonyl (>C0) or carbonylamino (-NH-CO-) groups or oxygen atoms at the ends and that optionally contains one or more oxygen atoms, 3-, acyl- or hydroxyacyl-substi-tuted imino groups or one or two C-C-double and/or 2 5 OC-triple bonds: (II) Z-N N-Z wherein D1 has the same meaning as Dc. except that D1 does not contain the substituent G, or D1 represents the - 79 - I 1 1 radical -CH-, =C- or -N-, and F~ has the same meaning as F, except that F~ does not contain the substituent G, or F1 represents the l i radical -CH- or =C-, 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 -CHjCOOY, 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 3,6,9,12,l8~pentaazabicyclo[12.3.1]octa~ deca-1(18),14,16-triene-M-tetraacetic acid or 3,6,9,15-tetraazabicyclo [9 . 3.1]pentadeca-1(15),11,13-triene-M-triacetic 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 21-2S, 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 l, characterised in that G represents a ring of the general formula II that is 2 5 bonded via a group -(CH2)i~s~# -0~(CH2)x-swO™' 00 0 0 1 u m 11 -C-(CH2)1-.6-C-f -CsC-C=C- or -NH-C- (CH? ) 0_6-C~NH- .

5. Pharmaceutical agents comprising at least one physiologically tolerable macrocyclic compound of the general formula I - 80 - 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=0, =MR2 , -CHR3- or =CR3-, E represents a nitrogen atom, a sulphur atomf an oxygen atom, the group =M (~, —C- or >MR4 , 0 ("" 1 OH, F represents (-CHR8-)n or (=CR8)n, R1 represents a hydrogen atom or a halogen atom or a Cj—Cg-alkyl group, Z represents a hydrogen atom or the group -CK2COOY 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 Ch-Cg-alkyl group, R3 represents a hydrogen atom or a halogen atom, a phenyl group or a C^-Cg-alky! group optionally substituted by one or mors phenyl and/or hydroxy groups,, or represents the radical OR5, the substituent ~(C)iMRsR7 or IS o the substituent G, R4 represents a hydroxy group, R2 or an optionally hydroxylated or carboxylated C^-Cg-alkyl group, R5 represents a C]_~Cg~alkyl radical optionally substituted by from l to 3 hydroxy groups, - 81 - Rs 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 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 R5, or one of the substituents R6 and R7 represents the radical 0 ~C~R5, R8 represents R1 or G, 1 represents the number 0 or 1, n represents the number 0 or 1, G represents a second raacrocvcle of the general formula II that is bonded via a direct bond, a bis(carbonylamino) group (-MH-CO-CO-NH-) or via a. cl~c20~alkYlene group that optionally carries carbonyl (>C0) or carbonylamino (-NH-CO-) groups or oxygen atoms at the ends and that optionally contains one or more oxygen atoms, Z-, acyl- or hydroxyacyl-substi-tuted imino groups or one or two C-C-double and/or C-C-triple bonds* r z-n A (II) D1 has the same meaning as D, except that D1 does not contain the substituent G, or D1 represents the 1 l 1 radical -CH-„ =C- or -N-, ana F1 has the same meaning as F, except that F1 does not contain the substituent G, or F1 represents the - 82 ~ I i 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 2 represent the radical -CroCOOY, and that tha macrocyelic compound of the general formula I does not contain more than one radical G, optionally together with additives customary in galenic pharmacy. 10 15 20 25

6. Use of at least one physiologically tolerable compound of the general formula X s-z (I), wherein .... represents a single bond 01 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=0, =NR2, -CHR3- or =CR3-, E represents a nitrogen atom, a sulphur atom, an oxygen atom, the group -N , =C~ or >NR4, o(~) OH, F represents (-CHR8-)n or (=CR8)n, R1 represents a hydrogen atom or a halogen atom or a Ci"*C6-alkyl group, Z represents a hydrogen atom or the group -CHgCOOY wherein ¥ represents a hydrogen atom and/or a metal - S3 - 10 i 5 ion equivalent of an alament of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83, R2 represents a hydrogen atom or a C^-Cg-alkyl group, R3 represents a hydrogen atom or a halogen atom, a phenyl group or a Cx-Cg-alkyI group optionally substituted by one or more phenyl and/or hydroxy groups, or represents the radical OR5, the substituent -(C)iNR6R7 or !! "" O the substituent G, R4 represents a hydroxy group, R2 or an optionally hydroxylated or carboxylated Ci~C6-alkyl group, R5 represents a Cx-Cg-alkyl radical optionally substituted by from 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 6-membered ring that optionally contains a further nitrogen, oxygen or sulphur atom or a carbonyl group and that is optio-2 0 nallv substituted by from 1 to 3 radicals R5, or one of the substituents R6 and R7 represents the radical 0 11 s -C-R5, R8 represents R1 or G, 1 represents the number 0 or l, 2 5 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 (-NH-CO-CO-NH-) or via, a Ci-C2o-alkylene group that optionally carries carbonyl 30 (>CQ) or carbonylamino ("MR-CO-) groups or oxygen atoms at the ends and that optionally contains one or more oxygen atoms, Z-, acyl- or hydroxyacyl-substi-tuted imino groups or one or two C-C-double and/or c-c-triple bonds: ~ 84 ~ Z wherein D~ has the same meaning as D, except that D1 doss not contain the substituent G, or D1 represents the 5 radical -i'H-, =C~ or -N-, and F1 has the same meaning as F, except that F1 does not contain the substituent G, or F1 represents the radical -CH- or =C~, and their salts with inorganic and/or organic bases, 10 amino acids or amino acid amides, with the provisos that at least two of the substituents Z represent the radical -CHjCOOY, that the macrocyclic compound of the general formula I does not contain more than one radical G, and that at least two of the substi-15 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 radio-2 0 diagnostics, radiotherapy or radiation therapy.

7. Process for the preparation of macrocyclic compounds of the general formula I RV°x t ** i A I 0 I - 85 - 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 atojaf the group =C=0, =NR2 f -CHR3- or =CR3-, E represents a nitrogen atom, a sulphur atom, an oxygen atom, the group =N ("** ^ -, =C- or >MR4, 0(") OH, F represents (-CHR8-)n or (=CR8)n, Rl represents a hydrogen atom or a halogen atom or a C1-C6-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, R2 represents a hydrogen atom or a Cj^-Cg-alkyl group, R3 represents a hydrogen atom or a halogen atom, a phenyl group or a Cx-Cs-alkyI group optionally substituted by one or more phenyl and/or hydroxy groups, or represents the radical OR5, the substituent ~(C)^NRSR7 or S o the substituent G, R4 represents a hydroxy group, R2 or an optionally hvdroxylated or carboxylated C;j_~Cg-alkyl group, R5 represents a Cj-Cg-slkyl radical optionally substituted by from 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 6-member@d ring that optionally contains a further nitrogen, oxygen or sulphur atom or a carbonyl group and that Is optio— as - nally substituted by from 1 to 3 radicals R5, or one of the substituents R6 and R' represents the radical ? 5 ~C™R5, R8 represents R1 or G, 5 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 zi& a direct bond, a bis(carbonylamino) group (-HS-CO-CO-NH-) or via a 10 Ci-C20=alkyiene group that optionally carries carbonyl (>CO) or carbonylamino (-MH-00-) groups or oxygen atoms at the ends and that optionally contains one or more oxygen atoms, Z-, acyl- or hydroxyacyl-substi-tuted imino groups or one or two C-C-double and/or 15 C-C-triple bonds: v v rv^. 2-H N-£ 1 A 1 q 2 wherein D1 has the same meaning as D, except that D1 does not contain the substituent G, or D1 represents the i i | 20 radical -CH-, =C- or HS-, asad F1 has the same meaning as F, except that F1 does not contain the substituent G# or F1 represents the « I radical -CH- or -c», fill and their salts with inorganic arsd/or organic bases, amino acids or amino acid asaides, with the provisos that at least v#o of the substituents Z represent the radical -CHjCsOOY, that the macrocyclic compound of the general forsaula I (floes not contain more 87 than one radieal G, and that the general formula I does not represent 3,6,9,12,18-pentaazabicyclo[12.3.1]octa-deca-i(is) ,l4,16~triene~H-tetraacetic acid or 3,6,9,15-tetraazabicyclo [9.3.1 ]pentadeca-1 (15) ,11,13-triene-N- triacetic acid or their Cu„ Pb, Co and Sr complexes, characterised in that compounds of the general formula I" i—x 1 H-N N-H L ) (i')/ nn-8) I q h wherein , :V°\ X represents :f or a 5- or 6-membered ring for Ac/V "E' 10 conversion into the desired ring, are alkylated in a manner known oer se with a halogen compound III HalCH2COOY' (III), wherein Hal represents chlorine, bromine or iodine and • 5 y represents a hydrogen atom or an acid-protecting group , and then, where appropriate after conversion of 1 into the desired 5- or S-memhered ring of the end product and, where appropriate, after removal of the protecting groups 20 v* t the resulting complexing agents of the general formula 1 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 . ara replaced with cations of inorganic and/or organic bases, amino acids or amino acid amides. - 88 -

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 for® 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. Dated this 19th day of July, 1989 CRUICKSHANK & CO Agents for the Applicant 1 Hoiles Street DUBLIN 2