IL91046A - Pharmaceutical and diagnostic compositions containing metal complexes of poly(carboxymethyl)-poly [azabicyclo (x,3,1) alkane] derivatives some new such derivatives and their preparation - Google Patents

Abstract

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

Description

91 046/4 PHARMACEUTICAL AND DIAGNOSTIC COMPOSITIONS CONTAINING METAL COMPLEXES OF POLY (CARBOXYMETHYL) -POLY [AZABICYCLO (X, 3,1) ALKANE] DERIVATIVES, SOME NEW SUCH DERIVATIVES, AND THEIR PREPARATION DDjDm ΠΊΚΏ m«rm nnu ] nioD 91046/2 - 1 - The invention relates to macrocyclic polyaza completing agents, polyaza complexes and polyaza complex salts containing 5 or 6 rings, media containing these compounds, their use as diagnostic and therapeutic media as well as processes for the production of these compounds and media.

Background of the Invention Metal complexes came into consideration as contrast media for radiology at the beginning of the 1950 's. But the compounds used at that time were so toxic, that their use in human beings was unsuitable. It was therefore completely surprising that certain complex salts have proven to be sufficiently compatible, so that a routine use in humans for diagnostic purposes could be considered. As the first representative of this class of substances, the dimeglumine salt of Gd-DTPA (gadolinium(III) complex of diethylene-triaminepentaacetic acid described in U.S. Patent No. 4,647,447 has proven its worth very well up to now as a contrast medium for nuclear spin tomography in clinical testing on over 7,000 patients. The main focus of use is for diseases of the central nervous system.

A significant reason for the good compatibility of Gd-DTPA in clinical use is in the high effectiveness in nuclear spin tomography, particularly with many brain tumors. Because of its good effectiveness, Gd-DTPA with 0.1 mmol/kg of body weight can be administered in much lower doses than, for example, X-ray contrast media in many X-ray examinations .

As another representative of the complex salts, the meglumine salt of Gd-DOTA (gadolinium (III) complex of 1,4,7, 10-tetraazacyclododecane-tetraacetic acid) described in German patent application 34 01 052 has proven itself for diagnostic purposes.

But now it is desired to use chelates at even higher doses. This is especially the case for detection of certain diseases outside the central nervous system with the aid of nuclear spin tomography (NMR diagnosis) , but particularly in the use of chelates as X-ray contrast media.

To keep the volume load of the body as small as possible, it is necessary to use highly concentrated chelate solutions. The chelates known until now are not very suitable for. this purpose, especially because of their exces-sively high osmolality.

There is therefore a need for chelates which exhibit a lesser osmolality than the previously known chelates.

However, at the same time the prerequisites for the use of these compounds on humans regarding the range between the effective dose and the toxic dose in animal testing (the therapeutic range) , the organ specificity, the stability, the contrast intensifying effect, the compatibility as well as the solubility of the complex compounds must be fulfilled.

Summary of the Invention Thus, an object of the invention is to make available compounds and media as described above, as well as to provide a process that is as simple as possible for their production.

Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.

These objects are attained by the compounds, media and processes according to the invention.

The complex compounds according to the invention and the solutions prepared from them fulfill the requirements mentioned in a surprising manner. They have a decreased osmolality as well as a more favorable therapeutic range and/or stability and storage property of the chemical components of the solution and/or organ specificity and/or contrast intensifying effect (e.g. relaxivity) and/or compatibility (e.g. decreased cardiovascular or allergy-like side effects) than the diagnostic media in use until now. ( Even without specific measures, their pharmacokinetics allows for an improvement in the diagnosis of numerous diseases. The complexes for the most part remain unchanged and are quickly excreted again, so that particularly even if relatively toxic metal ions are used, no harmful effects are observed despite high doses.

The practical use of the new complexes and complexing agents is also made easier by their favorable chemical stability.

An additional significant advantage of the described complexes and complexing agents is their extraordinary chemical versatility. Besides the central atom, the characteristics can be adapted to the requirements for effectiveness, pharmacokinetics, compatibility, solubility, manage- 91046/6 - 4 - ability etc. by the choice of diverse substituents, the 5 or 6 ring in the macrocycle and/or the counterions. Thus, for example, a very desirable specificity of the compounds for diagnosis and therapy can be obtained for structures in the organism, for certain biochemical substances, for metabolic processes and/or for conditions of tissues or body fluids.

The macrocylic compounds according to the invention are characterized by general formula I wherein .... represents a single bond or double bond; q is a number of 0 or l; A and B, being the same or different, are each straight-chain or branched c2-6 3*^Υΐβηβ group; D is N, 0, =C«0, >=NR2, -CHR3-, -CR3; E is N, S, 0, - or NR4; F is (-CHR8-)n or (=CR8-)n; Z is an H atom or the group -CHjCOOY with Y metal ion equivalents of at least one element with atomic numbers 21-29, 42, 44 or 57-83, or at least of one radionuclide of an element with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77; R1 is an H atom, a halogen atom, or a C^-C^ alkyl group; - 5 - 91046/8 Is H , Cj-C4 alkyl, R3 is H, a halogen atom, a plienyl or alkyl group, which alkyl group is optionally substituted by one or 5 6 7 more phenyl and/or hydroxy group(s); OR ; or -(CJ^NR R ; or G; 0 4 2 R is a hydroxy group, R or a c1_c4 alkyl group which is optionally hydroxylated or carboxylated; 5 R~ is a C -C- alkyl radical optionally substituted by 1 to 3 hydroxy groups; 6 7 R and R , independently from one another, are II, the radical R5, plienyl or benzyl radicals optionally substituted 6 7 by 1 to 3 hydroxy groups, or R and R together with the nitrogen atom form a saturated or unsaturated 5 or 6 members ring optionally containing an additional N atom, 0 atom, s atom or a carbonyl group, said 5 or 6 member ring being 5 optionally substituted by 1 to 3 radicals R , or one of the substituents R6 or R7 is -C-R5; and R'' are each independently C^- R is R or G; m is 0 or 1; n is 0 or 1; G is a second acrocycle of general formula II bonded by a direct bond, a bis (carbonylamino) group ( -NH-CO-CO-NH-) or by a c1~c2o aikylene group optionally having carbonyl (>CO) groups, carbonylamino' (-NH-CO-) groups, or 0 atoms on the ends thereof and optionally contains one or more oxygen atom(s) , Z-, C^^g-acyl groups, C1_10-hydroxyacy 1 substituted imino groups, one to two C-C double bonds and/or one to two C-C triple bonds - 6 - 91046/5 has the meaning as D, with the exception that does not stand for the radical -C IH-, or -NI-; and F1 has the same meaning as F, with the exception that F1 does not contain the substituent G, or stands for the radical -CM- or «=C-; as well as the salts thereof formed with inorganic and/or organic bases, amino acids or amino acid amides; with the proviso that at least two substituents z stand for the radical ~CH2C00Y and the macrocyclic compound of general formula I contains not more than one radical G, if n stands for the number 0 and the 5 member ring thus formed is to be unsaturated, then the double bonds are located between positions 2,3 and 4,5 of the 5 member ring, and said compound is neither 3 , 6 , 9-tris- (carboxymethy 1) -3 , 6 , 9 , 15- tetraazabicyclo(9,3,l)pentadeca-l(15) , 11 , 13-triene nor the Cu, Pb, Co and Sr complexes thereof.

The invention also provides a pharmaceutical media comprising at least one physiologically acceptable compound of general formula I wherein .... represents a single bond or double bond; q Is a number of 0 or 1; - 6A - 91046/5 Λ and Β, being the same or different, are each straight-chain or branched C. alkylene group; F is (-CHR8-)n or (=CR8-)n; Z is an II atom or the group -CII2C00Y with Y metal ion equivalents of at least one element with atomic numbers 21-29, 42, 44 or 57-83, or at least of one radionuclide of an element with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77; R1 is an II atom, a halogen atom, or a C^-C^ alkyl group; R2 is II, C^-c^ alkyl, R3 is H, a halogen atom, a phenyl or a C1~C4 alkyl group, which alkyl group is optionally substituted by one or 5 6 7 more phenyl and/or hydroxy group(s) ; OR ; or -(C) mNR R or G; 0 A R is a hydroxy group, R or a C^^-C^j alkyl group which is optionally hydroxylated or carboxylated; R5 is a C,-C, alkyl radical optionally substituted by 1 to 3 hydroxy groups; R6 and R7, independently from one another, are H, the radical R5, phenyl or benzyl radicals optionally substituted 6 7 by 1 to 3 hydroxy groups, or R and R together with the nitrogen atom form a saturated or unsaturated 5 or 6 members ring optionally containing an additional N atom, 0 atom, s atom or a carbo yl group, said 5 or 6 member ring being optionally substituted by 1 to 3 radicals R5, or one of the 0 Bubstituents R6 or R7 is -OR5; !?', R2 nnd '1 nre cncli independently C^-C^. ; R8 is R1 or G; C m is o or 1; n is 0 or 1; - 6B - 91046/2 G is a second macrocycle of general formula II bonded by a direct bond, a bis (carbonylamino) group (-NH-CO-CO-NH-) or by a c1~c2o alkylene group optionally having carbonyl (>CO) groups, carbonylamino (-NH-CO-) groups, or 0 atoms on the ends thereof and optionally contains one or more oxygen atom(s), Z-, C1_1Q-acyl groups, C1_1Q-hydroxyacyl substituted imino groups, one to two C-C double bonds and/or one to two C-C triple bonds D has the meaning as D, with the exception that not contain the substituent G, or stands for the radical -CH-, =C- or -N- ; and F1 has the same meaning as F, with the exception that F1 does not contain the substituent G, or stands for the radical -CH- or =C-; as well as the salts thereof formed with inorganic and/or organic bases, amino acids or amino acid amides; with the proviso that at least two substituents z stand for the radical -CH2C00Y and the macrocyclic compound of general formula I contains not more than one radical G, optionally with the additives usual in galenicals. - 7 - If the medium according to the invention is intended for use in NMR diagnosis, then the central ion of the complex salt must be paramagnetic. These are particularly the bivalent and trivalent ions of the elements with atomic numbers 21-29, 42, 44 and 58-70. Suitable ions are, e.g., the chromium(III) , manganese (III) , iron (II) , cobalt (II) , nickel(II), copper (II) , praseodymium (III) , neodymium(III) , samarium (III) and ytterbium (III) ions. Because of their strong magnetic moment the gadolinium (III) , terbium (III) , dysprosium (III) , holmium(III) , erbium(III) and iron(III) ions are particularly preferred.

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

If the medium according to the invention is intended for use in X-ray diagnosis, then the central ion must be derived from an element of a higher atomic number, to achieve sufficient absorption of the X-rays. It has been found that for this purpose diagnostic media which contain a physiologically compatible complex salt with central ions of elements with atomic numbers of 21-29, 42, 44, 57-83 are suitable; these are, for example, the lanthanum (III) ion and the above-mentioned ions of the lanthanide series.

As alkyl substituents R1, R2, R3 and R4, straight chain or branched hydrocarbons are suitable with up to 6, preferably up to 4 carbon atoms, which in the case of R3 are optionally substituted by one or more, preferably 1 to 3 , phenyl and/or hydroxy groups, in the case of R4 optionally by one or more, preferably 1 to 3, hydroxy or carboxyl groups, and in the case of R5 optionally by one or more, preferably 1 to 3 , hydroxy groups. 8 - Suitable optionally substituted alkyl groups are, for example, the methyl, hydroxymethyl , ethyl, 2-hydroxyethyl , 2-hydroxy-l- (hydroxymethyl) -ethyl , 1- (hydroxymethyl) -ethyl , propyl, isopropyl, 2- and 3-hydroxypropyl, 2 , 3-dihydroxy-propyl, n-, sec. -and tert. -butyl, 2-, 3- and -hydroxybutyl, 2- and 3- hydroxy-isobutyl, pentyl, 2-, 3- and 4-hydroxy-2-methylbutyl, 2,3,4-trihydroxybutyl, 1, 2 , 4-trihydroxybutyl , cyclopentyl, cyclohexyl, 2 , 3 , 4 , 5, 6-pentahydroxyhexyl , benzyl, carboxymethyl and carboxyethyl .

The halogen atom contained in R1 and R3 can be, for example, fluorine, chlorine, bromine and iodine.

The heterocyclic 5- or 6-membered ring formed by R6 and R7 with inclusion of the nitrogen atom can be saturated, unsaturated and/or substituted and optionally can contain a nitrogen atom, oxygen atom, sulfur atom or a carbonyl group.

Suitable heterocycles include, for example, the pyrrolidinyl, piperidyl, pyrazolidinyl, pyrrolinyl, pyra-zolinyl, piperazinyl, morpholinyl, imidazolidinyl, oxazoli-dinyl, thiazolidinyl , and pyrrolidonyl rings.

As alkylene groups A and B, straight chain or branched chains with 2 to 6 carbon atoms, preferably the ethylene, methylethylene and propylene groups are suitable.

The alkylene chain, on which the second macrocycle of formula II is bonded, carries on the ends optionally carbonyl (CO) , carbonylamino (NH-CO) groups or oxygen atoms' and contains 1-20 carbon atoms. It can be interrupted by one or more oxygen atoms(s), Z-, acyl or hydroxyacyl substituted imino groups or one to two C-C double bonds and/or C-C triple bonds. But both macrocycles can also be connected by a direct bond. As optionally hydroxylated acyl groups in this case, acyl radicals with up to 10 carbon atoms are suitable. For example the acetyl, propionyl, butyryl, benzoyl and hydroxyacetyl radical should be men- - 9 - 91046/2 tioned, species of optionally hydroxy-substituted hydrocarbonoyl of 1-10 carbon atoms.

The hydrocarbon chain can be straight chain or branched chain, saturated or unsaturated and optionally interrupted as described. It can contain up to 4 oxygen atoms and/or up to 3 carboxymethylimino groups.

Examples for the alkylene chain are: -(CH2)2-, -CH2-0-CH2- , -(CH2)4-f -(CH2-CH2-0-CH2-CH2)-, -(CH2-0-CH2)2-, -(CH2-0-CH2)3-, -CH2-CH2- (0-CH2-CH2) 3~ , -CH2-CH2-(0-CH2-CH2)4-, O O -CH2~CH-CH-CH2- -C=C-C≡C-, -NH-C- (CH2) „.6-C-NH OH OH 0 O -CH2-N-CH2-CH2-N-CH2-CH2-N-CH2-, -C-(CH2) j^-C-, -0-(CH2) ^-O-, CH> CH7 CH* COOH COOH COOH -CH2-N-CH2- , - (CH2) 2CH=CH- (CH2) z~ .

CO-CH2OH If not all acid hydrogen atoms are substituted by the central ion, one, several or all of the remaining hydrogen atom(s) can be replaced by cations of inorganic and/or organic bases or amino acids. Suitable inorganic cations are, e.g., the lithium ion, the potassium ion, the calcium ion, the magnesium ion and particularly the sodium ion.

Suitable cations of organic bases are, among others, those of primary, secondary or tertiary amines, for example such as ethanolamine, diethanolamine, morpholine, glucamine, N,N- - 10 - 91046/2 dimethylglucamine and particularly N-niethylglucamine .

Suitable cations of amino acids are for example those of lysine, arginine and ornithine.

The production of the macrocyclic complexes of general formula I according to the invention takes place, by compounds of general formula 11 being alkylated in the manner known in the in which X stands for or for a 5 or 6-membered ring to be converted into the desired ring, with a halogen compound of formula III HalCH2C0OY' (HI), in which Hal stands for chlorine, bromine or iodine and Y' stands for a hydrogen atom or an acid protecting grou , and then, optionally after conversion of X into the desired 5 or 6-membered ring of the end product and also optionally after cleavage of the protecting groups Y1, optionally the complexing agents of general formula I with Y meaning hydrogen thus obtained are reacted in the manner known in the art with at least one metal oxide or metal salt of an element with atomic numbers 21-29, 31, 32, 37-39, 42- 44, 49 or 57-83 and then, if desired, acid hydrogen atoms still present are substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides.

As acid protecting groups Y' lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, n- butyl, t-butyl, phenyl, benzyl, diphenylmethyl , triphenyl- - 11 - 91046/2 methyl, bis (p-nitrophenyl) methyl groups and trialkylsilyl groups are suitable.

The cleavage of protecting groups Y', which can be performed before or after conversion of X into the desired 5 or 6-membered ring of the end product, takes place according to the processes known to one skilled in the art, for example, by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous alcoholic solution at temperatures from 0 to 50°C or, in the case of tertiary butyl esters, with the help of trifluoroacetic acid, for example.

The alkylization of educts I1 with the halogen compounds of general formula III takes place in polar apro-tic solvents such as, e.g., dimethylformamide, acetonitrile , dimethyl sulfoxide, aqueous tetrahydrofuran or hexamethyl-phosphoric triamide in the presence of an acid catcher, such as, for example, a tertiary amine (e.g., triethylamine, trimethylamine or Ν,Ν-dimethylaminopyridine) , 1,5 diazabi-cyclo [4.3.0] nonene-5 (DBN) , 1,5 diazabicyclo [5.4.0] undecene-5 (DBU) , alkali, alkaline earth carbonate, hydrogen carbonate or hydroxide (e.g., sodium, magnesium, calcium, barium, potassium carbonate, hydroxide and hydrogen carbonate) at temperatures between -10°C and 120°C, preferably between 0°C and 50°C.

The conversion of a precursor of the desired 5- or 6-membered ring obtained in the end product takes place according to the methods known to one skilled in the art, for example, the hydrogenation of, e.g., pyridine- [Advan. Catal. 14, 203 (1963)], pyrrole- [M. Freifelder, Practical Catalytic Hydrogenation, 577, Wiley-Interscience, New York- London-Sydney-Toronto 1971], furan-[US-3 , 194 , 818 ] , pyrimi- dine-[J. Med. Chem. 15., 291 (1972)], deoxygenation of nitroxide-[E. Klingsberg, The Chemistry of Heterocyclic - 12 - 91046/2 Compounds, Volume 14, part 2, Interscience Publishers New York, p. 120 (1961)] rings, conversions and introduction of functional groups on the 5 or 6 member ring, e.g. , release of phenolic hydroxy groups [J. Org. Chem. 5 , 5 (1988)], introduction of halogen substituents [E. Klingsberg, The Chemistry of Heterocyclic Compounds, Volume 14, Part 2, Interscience Publishers New York, p. 341 (1961), Houben-Weyl, Methoden der organischen Chemie, Volume V/3, 651 (1962)], exchange of heteroatoms, e.g., conversion of a furan into a pyrrole (US-2 , 478 , 456) .

The functionalizing of 4-chloropyridine derivatives (e.g., azido exchange) in the phase transfer process with the use of 18-crown-6 or tetrabutyl ammonium bromide as a catalyst is described in "Phase Transfer Reactions" (Fluka Compendium vol. 2; Walter E. Keller, Georg Thieme Verlag, Stuttgart, New York) .

The production of amides, i.e. of compounds of general formula I which contain the group -NR6R7, e.g., in which R5 or R3 stands for -C-NR6R7, takes place by II o reaction of activated acid derivatives (e.g. mixed anhydride, acid chloride) with primary or secondary amines of the general formula in which R and R have the meaning given above.

As suitable amines the following should be mentioned as examples: di ethylamine, diethylamine , di-n-propylamine, diiso-propylamine, di-n-butylamine, diisobutylamine, di-sec-butylamine, N-methyl -n -propylamine, dioctylamine, dicyclo-hexylamine, N-ethylcyclohexylamine, diisopropenylamine, - 13 - 91046/2 benzylamine, aniline, 4-methoxyaniline, 4-dimethylamino- aniline, 3 , 5-dimethoxyaniline, morpholine, pyrrolidine, piperidine, N-methylpiperazine, N-ethylpiperazine, N-(2- hydroxyethyl)piperazine, 2- (2-hydroxymethyl) -piperidine, 4- (2-hydroxyethyl) -piperidine, 2-hydroxymethylpiperidine, 4- hydroxymethyl-piperidine, 2-hydroxymethyl-pyrrolidine, 3- hydroxypiperidine, 4-hydroxypiperidine, 3-hydroxy-pyrroli- dine, 4-piperidone, 3-pyrroline, 2 , 6-dimethylpiperidine, 2 , 6-dimethylmorpholine, pyrazoline, imidazoline, oxazoli- dine, thiazolidine, 2,3-dihydroxypropylamine, N-methyl-2 , 3- dihydroxypropylamine, 2-hydroxy-l-(hydroxymethyl) -ethyl-amine, N,N-bis-(2-hydroxyethyl) -amine, N-methyl-2 , 3 , 4 , 5, 6, -pentahydroxyhexylamine, 6-amino-2 , 2-dimethyl-l , 3-dioxepin-5 ol, 2-hydroxyethylamine, 2-amino-l,3-propanediol, diethanol amine, ethanolamine.

The polyhydroxyalkylamines can also be used advantageously in protected form for the reaction, for example, as 0-acyl derivatives or as ketals. This is especially the case, when these derivatives are easier and cheaper to produce than the polyhydroxyalkylamines themselves. A typical example is 2-amino-l- (2, 2-dimethyl-l, 3-dioxolan-4-yl)-ethanol, the acetonide of l-amino-2 , 3 , 4-trihydroxy-butane, produced according to DE-OS 31 50 917.

The subsequent removal of the protecting groups can also be performed by, for example, treatment with an acidic ion exchanger in aqueous ethanol solution. * The synthesis of compounds with more than one ring takes place according to processes known in the literature, for example by an addition/elimination reaction of an amine with a carbonyl compound (e.g. acid chloride, mixed anhydride, activated ester, aldehyde) ; of two amine substituted rings with a dicarbonyl compound (e.g. oxalyl chloride, glutaric dialdehyde) ; of two p-nitro substituted nitroxides - 14 - 91046/2 with bisalcoholates [cf. E. Klingsberg, The Chemistry of Heterocyclic Compounds, Interscience Publishers New York, p. 514 (1961)] of two rings, which each exhibit a nucleophilic group, with an alkylene compound carrying two leaving groups or in the case of terminal acetylenes by oxidative coupling (Cadiot. Chodkiewicz in Viehe "Acetylenes", 597-647, Marcel Dekker, New York, 1969) .

The chain connecting the rings can then be modified by consecutive reactions (hydrogenation, for example) .

The synthesis of the educts of general formula I' to be alkylated takes place by cyclization of two reactants, of which one contains the substituent X, i.e. the desired 5 or 6-membered ring of the end product or a precursor to be converted into it.

The cyclization is performed according to methods known in the literature, (for example Org. Synth. 58., 86 (1978) , Macrocyclic Polyether Syntheses, Springer Verlag, Berlin, Heidelberg, New York 1982, Coord. Chem. Rev. 3, 3 (1968), Ann. Chem. 1976. 916), J. Org. Chem, 49,110 [1984]): one of the two reactants carries on the end of the chain two leaving groups, the other contains two nitrogen atoms which displace these leaving groups in a nucleophilic manner. As an example there can be mentioned the reaction of terminal dichloro-, dibromo-, dimesyloxy-, ditosyloxy- or dialkoxy-carbonylalkylene compounds containing the substituent X and' optionally one to five nitrogen atoms with terminal diaza-alkylene compounds, optionally containing one to five additional nitrogen atoms in the alkylene chain. Instead, the substituent X can also be contained in the second reactant, i.e. the one with the terminal nucleophilic nitrogen atoms. The nitrogen atoms are optionally protected, for example as tosylates or trifluoroacetates and are released before the subsequent alkylization reaction according to processes known in the literature (the tosylates, e.g. with mineral acids, alkali metals in liquid ammonia, hydrobromic acid and phenol, RedAl®, lithium aluminum hydride, sodium amalgam, cf. , e.g., Liebigs Ann. Chem. 1977, 1344, Tetrahedron Letters 1976, 3477; the trifluoroacetates , e.g., with mineral acids or ammonia in methanol, cf. , e.g., Tetrahedron Letters 1967, 289) .

For the production of macrocycles substituted in various manners on the nitrogen atoms (hydrogen or the CH2COOY group) , these atoms can be provided in the educts with different protecting groups, e.g., with tosylate and benzyl groups. The latter are then also removed according to methods known in the literature, preferably by hydro-genation, e.g., EP Patent Application No. 232751).

If diesters are used in the cyclization reaction, then the diketo compounds thus obtained must be reduced according to processes known to one skilled in the art, for example with diborane.

Also, correspondingly, substituted terminal bis-aldehydes with each of the desired terminal bisamines can be cyclized. The reduction of the Schiff's bases thus obtained takes place according to methods known in the literature, e.g., by catalytic hydrogenation [Helv. Chim. Acta 61,1376 (1978)].

The production of the amines needed as initial substances for the cyclization takes place in a manner similar to' methods known in the literature.

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

The reaction of a diamine that can be obtained from amino acids (Eur. J. Med. Chem. -Chim. Ther. 21,333 (1986)) - 16 - with the double molar amount of an N-protected omega-amino acid yields a tetramine after suitable working up.

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

In both cases the number of carbon atoms between the N-atoms can be determined by the kind of diamines or amino acids used as coupling partners.

The compounds of general formula I thus obtained with Y meaning a hydrogen atom represent complexing agents. They can be isolated and purified or can be converted without isolation into metal complexes of general formula I with at least two of the substituents Y meaning a metal ion equivalent.

The production of the metal complexes according to the invention takes place in the manner, as it has been disclosed in the 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 (sulfate) of the element with atomic numbers 21-29, 31, 32, 37-39, 42-44, 57-83 in water and/or a lower alcohol (like methanol, ethanol or isopropanol) and reacting with the solution or suspension the equivalent amount of the complexing acid of general formula I with Y meaning a hydrogen atom, preferably at temperatures between 40 and 100°C, and then, if desired, substituting acid hydrogen atoms of acid groups present by cations of inorganic and/or organic bases, amino acids or amino acid amides.

The neutralization takes place in this case with the help of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, e.g., sodium, potassium, lithium, magnesium or calcium and/or organic bases such as, among others, primary, secondary and tertiary amines, such as, . - 17 - e.g., ethanolamine, morpholine, glucamine, N-methyl and N,N-dimethylglucamine, as well as basic amino acids, such as lysine, arginine and ornithine, for example.

For the production of the neutral complex compounds, for example, as much of the desired bases can be added to the acid complex salts in aqueous solution or suspension that the neutral point is reached. The solution obtained can then be evaporated to dryness in a vacuum. Often it is advantageous to precipitate the neutral salts formed by addition of water-miscible solvents, as for example lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others) , polar ethers (tetrahydrofuran, dioxane, 1, 2-dimethoxyethane and others and thus to obtain crystallizates easy to isolate and purify. It has been shown to be especially advantageous to add the desired base to the reaction mixture during the complexing, thereby saving a processing step.

If the acid complex compounds contain several free acid groups, then it is often expedient to produce neutral mixed salts, which contain both inorganic and organic counterions as ions of opposite charge.

This can take place, e.g., by reacting the complexing acid in aqueous suspension or solution with the oxide or salt of the element yielding the central ion and half of the amount of an organic base needed for the neutralization, by" isolating the complex salt formed, purifying it if desired, then mixing it for complete neutralization with the needed amount of inorganic base. The order of addition of the bases can also be reversed.

In the case of the use of complex compounds containing radioisotopes, their production can be performed according to the methods described in "Radiotracers for - 18 - Medical Applications," Volume 1, CRC-Press, Boca Raton, Florida.

The production of pharmaceutical media according to the invention also takes place in a way known in the art, whereby the complex compounds according to the invention — optionally with the addition of the additives usual in galenicals — are suspended or dissolved in aqueous medium and then the suspension or solution is optionally sterilized. Suitable additives are, for example, physiologically harmless buffers (as for example tromethamine) , small additions of complexing agents (as for example diethylenetriaminepentaacetic acid) or, if necessary, electrolytes such as for example sodium chloride or, if necessary, antioxidants as for example ascorbic acid.

If for enteral administration or other purposes suspensions or solutions of the media according to the invention in water or physiological saline solution are desired, they are mixed with one or more adjuvants usual in galenicals (e.g. methylcellulose, lactose, mannitol) and/or surfactant (s) (for example, lecithin, Tween®, Myrj® and/or aromatic substance (s) for taste modification (for example ethereal oils) In principle it is also possible to produce the pharmaceutical media according to the invention even without isolation of the complex salts. In any case particular care must be used to perform the chelate formation so that the salts and salt solutions according to the invention are virtually free of uncomplexed metal ions with toxic effects.

This can be ensured, for example, with the help of color indicators such as xylenol orange, by control titration during the production process. The invention therefore relates also to processes for the production of the complex compounds and their salts. As a final safety - 19 - measure, purification of the isolated complex salt can be conducted.

The pharmaceutical media according to the invention preferably contain about 1 micromol/1 - 1 mol/1 of the complex salt and are as a rule dosed in amounts of about 0.001 - 5 mmol/Jg of body weight. They are intended for enteral and parenteral application. The complex compounds according to the invention can be used 1. for NMR and X-ray diagnosis in the form of their complexes with the ions of the elements with atomic numbers 21-29, 42, 44 and 57-83; and 2. for radiodiagnosis and radiotherapy in the form of their complexes with the radioisotopes of the elements with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 and 77.

The media according to the invention fulfil the diverse prerequisites for suitability as contrast media for nuclear spin tomography. Thus, they are eminently suitable, after oral or parenteral application, to improve the meaningfulness of the image obtained with the help of the nuclear spin tomograph by increasing the signal intensity. Further, they show the high effectiveness that is necessary to load the body with the smallest possible amounts of foreign substances, and the good compatibility that is necessary to maintain the noninvasive character of the examinations.

The good water solubility and negligible osmolality of the media according to the invention make it possible to produce highly concentrated solutions, to keep the volume load of the circulation within justifiable limits and to balance the dilution by the body fluids. In other words, NMR diagnostic media must be 100 to 1000 times more water - 20 - soluble than agents used for NMR spectroscopy. Furthermore, the media according to the invention exhibit not only a high stability in vitro, but also a surprising stability in vivo, so that a release or an exchange of the ions not covalently bonded in the complexes — and toxic in themselves — takes place only very slowly and within which time the new contrast media are completed excreted.

In general the media according to the invention are dosed for use as NMR diagnostic media in amounts of about 0.001 - 5 mmol/kg of body weight, preferably 0.005 - 0.5 mmol/kg. Details of use are discussed, for example, in H.J.

Weinmann et al., Am. J. of Roentgenology 142. 619 (1984).

Especially low dosages (under 1 mg/kg of body weight) of organ specific NMR diagnostic media can be used for example for the detection of tumors and of myocardial infarction.

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

The media according to the invention, on account of their favorable' radioactive characteristics and the good stability of the complex compounds contained in them, are also suitable as radiodiagnostic media. Details of the use and dosage of radiodiagnostic media are described, e.g., in "Radiotracers for Medical Applications," CRC-Press, Boca Raton, Florida.

A further imaging method with radioisotopes is positron emission tomography which uses positron emitting isotopes such as, e.g., Sc, Sc, Fe, Co and Ga.

(Heiss, W.D., Phelps, M.E., Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983) . - 21 - The compounds according to the invention can also be used in radioimmuno or radiation therapy. This is distinguished from the corresponding diagnosis only by the amount and kind of isotope used. In this case the objective is the destruction of tumor cells by energy rich shortwave radiation with the smallest possible range. Suitable beta- AC A7 AQ 7 Ύ¾ emitting ions are, for example, Sc, Sc, Sc, Ga and Ga. Suitable alpha-emitting ions exhibiting small half-life periods are, for example, 211Bi, 212Bi, 213Bi, 21Bi, and 12Bi is preferred. A suitable photon and electron emitting ion is 158Gd, which can be obtained from 157Gd by neutron capture.

With in vivo application of the therapeutic media according to the invention, they can administered together with a suitable vehicle as, for example, serum or physiological saline solution and together with another protein as, for example, human serum albumin. Here, the dosage is dependent on the kind of cellular disturbance, the metal ion used and the kind of imaging method.

The therapeutic media according to the invention are applied parenterally, preferably i.v. (intravenously) .

Details of the use of radiotherapeutic media are discussed, e.g., in .W. ozak et al., TIBTEC, October 1986, 262.

The media according to the invention are eminently suitable as X-ray contrast media, and it should be ' especially emphasized that, with the media according to the invention, no symptoms of the well known anaphylaxis type reactions to contrast media containing iodine are observed. They are especially valuable because of the good absorption characteristics in areas of higher tube voltages for digital substraction techniques. - 22 - In general the media according to the invention for use as X-ray contrast media are dosed in analogy to meglumine-diatrizoate, for example, in amounts of about 0.1 - 5 mmol/kg, preferably 0.25 - 1 mmol/kg.

Details of the use of X-ray contrast media are discussed, for example, in Barke, Roentgenkontrastmittel (X-ray Contrast Media) , G. Thieme, Leipzig (1970) and P. Thurn, E. Buecheler- "Einfuehrung in die Roentgendiagnostik" (introduction to X-ray Diagnosis) , G. Thieme, Stuttgart, New York (1977) .

Overall there has been success in synthesizing new complexing media, metal complexes and metal complex salts, which open up new possibilities in diagnostic and therapeutic medicine. Especially the development of novel imaging processes in medical diagnosis makes this development appear desirable.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.

The entire texts of all applications, patents, and publications cited above and below, and of corresponding application Federal Republic of Germany P 38 25 040.3, filed July 20, 1988, are hereby incorporated by reference.

The following examples will provide more detailed explanation of the object of the invention. - 23 - EXAMPLE 1 a) 3,6, 9-tris (p-tolylsulfonyl) -3,6,9, 15-tetraazabicyclo-[9 , 3 , l]pentadeca-l (15) , 11, 13-triene A solution of 35.2 g (200 mol) of 2 , 6-bis- (chloro-methyl) -pyridine (dissolved in 700 ml of dimethyIformamide) is instilled into 121.9 g (200 mol) Ν,Ν' ,N"-tris (p-tolylsul-fonyl) -diethylenetriamine-N,N"-disodium salt in 1600 ml of dimethylfor amide at 100°C within 3 hours. It is stirred overnight at 100°C. Into the hot solution 2 1 of water is instilled and it is cooled to 0°C. The precipitate is suctioned off and washed with water. After drying in a vacuum (60°C) it is recrystallized from acetonitrile. 92.3 g (69% of theory) of the title compound is obtained as colorless powder.

Analysis: Calculated: C 57.46 H 5.43 N 8.38 O 14.35 S 14.38 Found: C 57.39 H 8.35 N 5.48 S 14.34 b) 3 , 6 , 9 , 15-tetraazabicyclo[9.3. l]pentadeca-l (15) ,11, 13-triene tetrahydrosulfate 90.3 g (135 mmol) of the title compound from example la is added into 270 ml of concentrated sulfuric acid and stirred 48 hours at 100°C. It is cooled to 0°C and 1.35 1 of absolute ether is instilled into it. The precipitate is suctioned off and absorptively precipitated in 800 ml of methanol. After filtration and concentration by evaporation it is dried in a vacuum at 50°C.

Yield: 42.6 g (52.7% of theory) of a solid melting in the air.

Analysis: Calculated: C 22.07 H 4.38 N 9.36 O 42.76 S 21.43 Found: C 22.10 H 4.42 N 9.31 S 21.40 - 24 - 91046/2 c) 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15) ,11,13-triene 40.0 g (66.8 mmol) of the title compound from example lc is dissolved in 100 ml of water and is adjusted to pH 11 with 32% sodium hydroxide solution. It is extracted 8 times with 150 ml of methylene chloride and dried on magnesium sulfate. After concentration by evaporation in a vacuum, 9.79 g (71% of theory) of a yellowish powder is obtained. Analysis: Calculated: C 64.04 H 8.79 N 27.16 Found: C 63.91 H 8.85 N 26.98 d) 3,6, 9-tris- (carboxymethyl) -3,6,9, 15-tetraazabicyclo-[9.3. l]pentadeca-l (15) , 11, 13-triene 33.1 g (55.1 mmol) of the title compound from example lc is adjusted to pH 8.5 in 170 ml of water with 6 N potassium hydroxide solution. To this solution 20.84 g (220.5 mmol) of chloroacetic acid is added, adjusted with 6 N potassium hydroxide solution to pH 9.5 and heated to 45°C. It is stirred at this temperature for 12 hours and the pH is kept between 9.5-10 by addition of 6 N potassium hydroxide solution. After cooling to room temperature, it is adjusted to pH 2 with concentrated hydrochloric acid and is evaporated to dryness. The residue is extracted with 300 ml of ethanol/50 ml of acetone, the solid is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is dissolved in a little water and poured onto a cation exchanger column (IR 120) . After rinsing with water the ligand is eluted with 0.5 N aqueous ammonia solution. The fractions are concentrated by evaporation, taken up with a little water and poured on an anion exchanger column (IRA 67). It is first washed with water and then eluted with 0.5 N formic acid. It is concentrated by evaporation in a vacuum and the residue is dissolved in a little hot ethanol. By careful addition of acetone and cooling in the ice bath the title compound is crystallized out.

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

Analysis: Calculated: C 53.67 H 6.36 N 14.73 0 25.24 Found: C 53.55 H 6.43 N 14.65 e) Gadolinium complex of 3,6,9-tris-(carboxymethyl) -3,6,9, 15-tetraazabicyclo-[9 · 3. l]pentadeca-l (15) ,11, 13-triene 5.0 g (13.14 mmol) of the title compound from example Id is dissolved in 20 ml of deionized water and 2.38 g (6.57 mmol) of gadolinium oxide is added. It is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried.

Yield: 7.74 g (100% of theory) of a white amorphous powder, which according to analysis contains 9.31% water. Analysis: Calculated: C 38.19 H 3.96 N 10.46 0 17.98 Gd 29.41 Found: C 38.11 H 4.05 N 10.38 Gd 29.32 The following relaxivity was measured in the plasma (the measurements of relaxation times Tl took place in a minispec p20 (Bruker) at 0.46 tesla (=20MHz) at 40°C: T2 relaxivity: 7.64 (L/mmol sec) In comparison: dimeglumine salt of the gadolinium complex of diethylenetriaminepentaacetic acid (Gd-DPTA) : Tj relaxivity: 4.95 (L/mmol sec) Osmolality of a 0.5 molar solution at 37°C: 0.55 (Osml/kg of water) In comparison: dimeglumine salt of Gd-DTPA: 1.1 (Osml/kg of water) . - 26 - In a similar way with iron(III) oxide, Fe203, the iron (III) complex of 3 , 6, 9-tris (carboxymethyl) -3 , 6, 9 , 15-tetraazabicyclo- [9.3.1] -pentadeca-1 (15) , 11, 13-triene is obtained as brown powder.

Analysis (relative to anhydrous substance) Calculated: C 47.13 H 4.89 N 12.83 Fe 12.89 Found: C 47.04 H 4.96 N 12.84 Fe 12.81 Tj relaxivity (L/mmol . sec) , 40°C, water, 20 MHz: 0.49 f) Dysprosium complex of 3, 6, 9-tris- (carboxymethyl)-3,6,9, 15-tetraazabicyclo [9.3.1]pentadeca-1 (15) , 11 , 13-triene If instead of gadolinium oxide in example le dysprosium oxide is used, the title compound is obtained virtually in quantitative yield.

Analysis: Calculated: C 37.82 H 3.92 N 10.38 O 17.78 Dy 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-tetraazabicyclo [9.3.1]pentadeca-1 (15) , 11, 13-triene If instead of gadolinium oxide in example le ytterbium oxide is used, the title compound is obtained virtually in quantitative yield.

Analysis: , Calculated: 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 manganese (II) complex of 3,6,9-tris-(carboxymethyl) -3,6,9, 15-tetraazabicyclo [9.3. l]pentadeca-1(15) , 11, 13-triene 3.0 g (7.89 mmol) of the title compound from example Id is dissolved in 20 ml of deionized water and 907 mg (7.89 mmol) of manganese (II) carbonate is added. It 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-methylglucamine solution. Then it is freeze-dried.

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

Analysis: Calculated: C 45.86 H 6.25 N 11.14 O 28.00 Mn 8.74 Found: C 45.98 H 6.21 N 11.08 Mn 8.68 EXAMPLE 2 a) 3,6, 9-tris- (carboxymethyl) -3 ,6,9, 15-tetraazabicyclo-[9.3.1] pentadecane 6.0 g (15.77 mmol) of the title compound from example Id is dissolved in 200 ml of 5% hydrochloric acid and hydro-genated in an autoclave on a rhodium catalyst (5% Rd/C) at 30 bars, 45°C. After 4 hours it is filtered from the catalyst and concentrated by evaporation in a vacuum. The residue is purified in ion exchangers as described in example Id. Crystallization from methanol/acetone yields 4.75 g (78% of theory) of an extremely hygroscopic compound.

Analysis: Calculated: C 52.83 H 7.83 N 14.50 O 24.84 Found: C 52.94 H 7.89 N 14.37 d) Gadolinium 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 is added to 4.3 g (11.13 mmol) of the title compound from example 2a in 20 ml of deionized water and is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried. 6.5 g (100% of theory) of a white, flaky powder is obtained, which according to analysis contains 10.3% water.

Analysis: Calculated: C 37.76 H 5.03 N 10.36 O 17.76 Gd 29.08 Found: C 37.63 H 5.12 N 10.33 Gd 28.97 EXAMPLE 3 a) 3,6, 9-tris (acetyl) -3,6,9, 15-tetraazabicyclo[9.3. l]penta-deca-l(15) , 11, 13-triene 15.8 g (78.6 mmol) of the title compound from example lc, 42.7 ml of triethylamine (306.4 mmol) and 50 mg of dimethylaminopyridine (DMAP) are dissolved in 300 ml of absolute methylene chloride. 28.9 ml (306.4 mmol) of acetic anhydride is added and it is stirred overnight at room temperature. The solvent is concentrated by evaporation in a vacuum and the residue is taken up with 200 ml of 3% sodium carbonate solution. It is extracted 2 times with 150 ml of methylene chloride. After drying of the organic phase on magnesium sulfate it is concentrated by evaporation in a vacuum. The residue is recrystallized from ether/ethyl acetate. 23.93 g (94% of theory) of the title compound is obtained as white flakes.

Analysis: Calculated: C 61.42 H 7.28 N 16.86 0 14.44 Found: C 61.48 H 7.37 N 16.80 b) 3 , 6, 9-tris (acetyl) -3,6,9, 15-tetraazabicyclo[9.3. l]penta-deca-1 (15) , 11, 13-triene-15-N-oxide 22.5 g (67.7 mmol) of the title compound from example 3a is dissolved in 100 ml of glacial acetic acid. 7.7 ml of a 30% hydrogen peroxide solution is added and heated for 4 hours to 70°C. Then an additional 3.9 ml of 30% hydrogen peroxide solution is added and it is stirred an additional hour at 70°C. It is concentrated by evaporation in a vacuum to a third and is carefully mixed with saturated sodium - 29 - 91046/2 carbonate solution until the alkaline reaction. It is extracted twice with 250 ml of methylene chloride and then the organic phases are dried on magnesium sulfate. After concentration by evaporation in a vacuum and crystallization from ether/ethyl acetate, 18.63 g (79% of theory) of the title compound is obtained as crystalline powder.

Analysis: Calculated: C 58.60 H 6.94 N 16.08 0 16.07 Found: C 58.47 H 6.88 N 16.14 c) 13-nitro-3 , 6 , 9-tris (acetyl) -3 , 6 , 9 , 15-tetraazabicyclo- [9.3. l]pentadeca-l (15) , 11, 13-triene-15-N-oxide 17 g (48.8 mmol) of the title compound from example 3b is dissolved in 40 ml of 90% sulfuric acid and heated to 60°C. To this solution 14 ml of concentrated nitric acid (d=1.36) is instilled and is stirred for 3 hours at 60°C.

It is poured on ice, the precipitate is filtered and it is washed with much water. After drying in a vacuum an orange powder is obtained, which is recrystallized from acetone.

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

Analysis: Calculated: C 51.90 H 5.89 N 17.80 O 24.40 Found: C 52.01 H 5.76 N 17.64 d) 13 , 13 ' -ethylenedioxy-bis [3 , 6 , 9-tris- (acetyl) -3,6,9,15-tetraazabicyclo[9.3.1 ] pentadeca-1 (15) , 11, 13-triene-15-N-oxide] A freshly prepared solution of ethylene glycol di-sodium in dimethylformamide produced from 620 mg of ethanediol and 600 mg of sodium hydride (80% suspension in paraffin oil) in 15 ml of anhydrous dimethylformamide is instilled within 10 minutes in a 50°C warm solution of 8 g (20.34 mmol) of the title compound from example 3c and is stirred overnight at this temperature. 10 ml of water is added and it is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methanol/32% aqueous ammonia solution: 10/1) . After crystallization from ether/ethyl acetate 3.15 g (41% of theory) of a yellowish crystalline powder is obtained.

Analysis: Calculated: C 57.28 H 6.68 N 14.85 0 21.19 Found: C 57.40 H 6.61 N 14.79 e) 13,13' -ethylenedioxy-bis [3,6, 9-tris- (acetyl) -3,6,9, 15-tetraazabicyclo [9.3.1] pentadeca-1 (15) , 11, 13-triene] 3 g (3.97 mmol) of the title compound from example 3d is dissolved in 100 ml of ethanol, 1 ml of concentrated hydrochloric acid is added and hydrogenated on Pd/C. It is filtered from the catalyst, concentrated by evaporation in a vacuum and the residue is taken up with 50 ml of a 3% sodium carbonate solution. It is extracted twice with 100 ml of methylene chloride. After drying of the organic phases on magnesium sulfate, the solvent is removed in a vacuum and is crystallized from ether/ethyl acetate.

Yield: 2.87 g (87% of theory) of white flakes Analysis: Calculated: C 59.81 H 6.97 N 15.50 O 17.71 Found: C 59.70 H 6.91 N 15.39 f) 13,13 '-ethylenedioxy-bis [3,6,9, 15-tetraazabicyclo-[9.3. l]pentadeca-l (15) , 11, 13-triene 2.5 g (3.46 mmol) of the title compound from example 3e and 4.66 g (41.5 mmol) of potassium tert. -butylate are dissolved in 40 ml of dioxane under nitrogen and refluxed overnight. It is concentrated by evaporation in a vacuum, the residue is taken up with 50 ml of water and it is - 31 - 91046/2 brought to pH 10 with 2 N sodium hydroxide solution. After extraction 6 times with 80 ml of methylene chloride each time, it is dried on magnesium sulfate and the solvent is removed in a vacuum.

Yield: 1.55 g (95% of theory) of a pale yellow oil, which crystallizes when allowed to stand.

Analysis : Calculated: C 61.25 H 8.14 N 23.81 O 6.80 Found: C 61.17 H 8.20 N 23.93 g) 13 , 131 -ethylenedioxy-bis [3,6, 9-tris- (carboxymethyl) -3,6,9, 15-tetraazabicyclo[9.3. l]pentadeca-l (15) ,11, 13-triene] 1.4 g (2.97 mmol) of the title compound from example 3f is dissolved in 20 ml of water and 2.25 g (23.8 mmol) of chloroacetic acid is added. With 6 N potassium hydroxide solution it is adjusted to pH 9.5. It is stirred for 12 hours at 45°C and the pH is maintained between 9.5-10 by addition of 6 n potassium hydroxide solution. It is brought to pH 2 with concentrated hydrochloric acid and is purified on ion exchangers as described in example Id. Crystallization from ethanol/acetone yields 1.3 g (57% of theory) of the title compound as a strongly hygroscopic solid.

Analysis : Calculated: C 52.80 H 6.16 N 13.69 0 27.35 Found: C 52.67 H 6.07 N 13.75 h) gadolinium complex of 13 , 131 -ethylenedioxy-bis [ 3 , 6 , 9-tris (carboxymethyl) -3,6,9, 15-tetraazabicyclo[9.3.1] penta-deca-l(15) , 11 , 13-triene] 1.2 g (1.47 mmol) of the title compound from example 3g is dissolved in 8 ml of deionized water and 533 mg (1.47 mmol) of gadolinium oxide is added. It is stirred for 3 - 32 - hours at 90°C. The solution is filtered and the filtrate is freeze-dried.

Yield: 1.85 g (100% of theory) of an amorphous powder, which according to analysis contains 11.3% water. Analysis: Calculated: C 38.45 H 3.93 N 9.94 0 19.87 Gd 27.90 Found: C 38.60 H 3.98 N 10.03 Gd 27.79 EXAMPLE 4 a) 13-ethiny1-3 ,6,9-tris (carboxymethyl) -3 , 6 , 9 , 15-tetraaza-bicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene-15N-oxide 10 g (25.42 mmol) of the title compound from example 3c is dissolved in 200 ml of dimethoxyethane (DME) under nitrogen. 1.22 g (25.42 mmol) of sodium acetylide (18% suspension in xylene/1ight mineral oil) is added and it is stirred overnight at room temperature. 10 ml of water is added and it is evaporated to dryness. The residue is chromatographed on silica gel (mobile solvent: methanol/acetone = 1:1). Crystallization from ether/ethyl acetate yields 5.02 g (53% of theory) of the title compound as a bright yellow powder.

Analysis: v . - Calculated: C 61.27 H 6.49 N 15.05 O 17.19 Found: C 61.31 H 6.55 N 14.94 b) 13, 13· -(1.3-butadiyne-1 , 4-diyl) -bis ([3,6, 9-tris-(acetyl) -3 ,6,9 , 15-tetraazabicyclo[9.3. l]pentadeca- 1 ( 15) , 11 , 13-triene] -15-N-oxide) 4.75 g (12.75 mmol) of the title compound from example 4a is dissolved in 200 ml of pyridine and reacted with 2.52 g (25.5 mmol) of copper (I) chloride. The solution is saturated with oxygen and then stirred for two days at room temperature. Here it must be guaranteed that an oxygen - 33 - atmosphere is constantly maintained. After concentration of the solution by evaporation in a vacuum, the residue is chromatographed on silica gel (mobile solvent: methanol/-acetone = 1/2) . Crystallization from ether/ethyl acetate yields 2.7 g (57% of theory) of a weakly yellowish powder. Analysis: Calculated: C 61.27 H 6.49 N 15.05 O 17.19 Found: C 61.31 H 6.55 N 14.94 c) 13 , 13 '-(1, 3-butadiyne-l,4-diyl) -bis[3,6,9-tris-(acetyl) -3,6,9, 15-tetraazabicyclo [9.3.1]pentadeca-1 (15) , 11 , 13-triene] 2.5 g (3.37 mmol) of the title compound from example 4b is dissolved in 50 ml of glacial acetic acid and heated to 60°C. 1.88 g (33.65 mmol) of iron powder is added and it is stirred for 2 hours at 60°C. It is filtered from the solid and the filtrate is evaporated to dryness. The residue is taken up with 100 ml of 3% sodium carbonate solution and extracted three times with 100 ml of chloroform. After frying on magnesium sulfate the solvent is removed in a vacuum and it is crystallized from ether/acetone.

Yield: 2.08 g (87% of theory) colorless powder Analysis: Calculated: C 64.21 H 6.52 N 15.77 O 13.51 Found: C 64.31 H 6.60 N 15.68 d) 13 , 131 - ( 1 , 3-butadiyne-l , 4-diyl) -bis [3,6,9, 15-tetraazabicyclo [9.3.1]pentadeca-1 (15) , 11, 13-triene] 1.9 g (2.67 mmol) of the title compound from example 4c is dissolved in 20 ml of dioxane under nitrogen. 2.4 g (21.38 mmol) of potassium tert . -butylate is added and it is refluxed overnight. The solvent is removed in a vacuum and the residue is taken up with 20 ml of water. It is adjusted - 34 - 91046/2 with 2 N sodium hydroxide solution to pH 10 and is extracted six times with 60 ml of methylene chloride. After drying of the organic phases on magnesium sulfate it is concentrated by evaporation in a vacuum.

Yield: 1.09 g (89% of theory) of a pale yellow oil. Analysis : Calculated: C 68.09 H 7.47 N 24.44 Found: C 68.18 H 7.54 N 24.51 e) 13 , 13 ' -(1, 3-butadiyne-l, 4-diyl) -bis [3 , 6, 9-tris- (carboxy-methyl) -3,6,9, 15-tetraazabicyclo [9.3. l]pentadeca- 1(15) , 11, 13-triene] 1.0 g (2.18 mmol) of the title compound from example 4d is dissolved in 15 ml of water and 1.65 g (17.44 mmol) of chloroacetic acid is added. It is adjusted with 6 N potassium hydroxide solution to pH 9.5 and stirred for 12 hours at 45°C. Here the pH is maintained between 9.5-10 by addition of 6 N potassium hydroxide solution. After acidifying with concentrated hydrochloric acid it is purified on ion exchangers as described in id. Crystallization from metha-nol/acetone yields 1.07 g (61% of theory) of a strongly hygroscopic solid.

Analysis : Calculated: C 56.57 H 5.75 N 13.89 O 23.79 Found: C 56.64 H 5.81 N 13.79 f) Gadolinium complex of 13 , 131 - (1, 3-butadiyne-l, 4-diyl) -bis [3 , 6 , 9-tris (carboxymethy1) -3,6,9, 15-tetraazabicyclo-[9.3.1] entadeca-1 ( 15 ) , 11 , 13-triene ] 900 mg (1.116 mmol) of the title compound from example 4e is dissolved in 8 ml of water and 404 mg (1.116 mmol) of gadolinium oxide is added. After three hours of stirring at 90°C the solution is filtered and the filtrate is freeze-dried.

Yield: 1.35 g (100% of theory) of a white amorphous powder, which according to analysis contains 8.9% of water. Analysis: Calculated: C 40.92 H 3.62 N 10.05 0 17.22 Gd 28.20 Found: C 40.81 H 3.65 N 10.18 Gd 28.11 EXAMPLE 5 a) 13-chloro-3 , 6 , 9-tris (acetyl) -3 ,6,9, 15-tetraazabicyclo- [9.3.1] pentadeca-1 ( 15) , 11 , 13-triene-15-N-oxide 7.3 g (18.56 mmol) of the title compound from example 3c is heated in 50 ml of acetyl chloride for 4 hours to 50°C. It is concentrated by evaporation in a vacuum and the residue is taken up in 200 ml of 3% sodium carbonate solution. It is extracted three times with 100 ml of chloroform and dried on magnesium sulfate. After removal of the solvent in a vacuum, it is re-crystallized from ether/ethyl acetate.

Yield: 6.18 g (87% of theory) of a colorless cry- I stalline powder.

Analysis: Calculated: C 53.33 H 6.05 N 14.64 O 16.72 CI 9.26 Found: C 53.48 H 5.98 N 14.71 CI 9.20 b) 13-chloro-3 , 6, 9-tris (acetyl) -3,6,9, 15-tetraazabicyclo- [9.3. l]pentadeca-l (15) , 11, 13-triene i 6.0 (15.67 mmol) of the title compound from example 5a is dissolved in 300 ml of ethanol. 1 ml of concentrated hydrochloric acid is added and it is hydrogenated on Pd/C. After hydrogen absorption is finished, it is filtered from the catalyst and concentrated by evaporation in a vacuum. The residue is taken up with 100 ml of 3% sodium carbonate - 36 - 91046/2 solution and extracted twice with 100 ml of chloroform. The organic phases are dried on magnesium sulfate and concentrated by evaporation in a vacuum. Crystallization of the residue from ether/acetic acid yields 5.34 g (93% of theory) of the title compound as a colorless powder.

Analysis : Calculated: C 55.66 H 6.32 N 15.27 O 13.08 CI 9.66 Found: C 55.57 H 6.38 N 15.31 Cl 9.59 c) 13-chloro-3, 6,9, 15-tetraazabicyclo [ 9.3. l]pentadeca-1(15) , 11, 13-triene 5.1 g (13.9 mmol) of the title compound from example 5b is dissolved in 50 ml of dioxane under nitrogen. 6.24 g (55.6 mmol) of potassium tert . -butylate is added and it is refluxed overnight. It is worked up as described in example 4d.

Yield: 3.01 g (90% of theory) of a slightly yellowish oil, which crystallizes after a short time.

Analysis : Calculated: C 54.88 H 7.12 N 23.28 Cl 14.73 Found: C 54.93 H 7.06 N 23.41 Cl 14.81 d) 13-chloro-3 , 6 , 9-tris (carboxymethyl) -3,6,9, 15-tetraaza-bicyclo[9.3. l]pentadeca-l (15) ,11, 13-triene 2.38 g (11.65 mmol) of the title compound from example 5c is dissolved in 30 ml of water and 4.4 g (46.6 mmol) of chloroacetic acid is added. It is adjusted to pH 9.5 with 6 potassium hydroxide solution. It is stirred for 12 hours at 45°C and the pH is maintained between 9.5-10 by addition of 6 N potassium hydroxide solution. After working up as described in example Id and crystallization from methanol/acetone, 3.23 g (67% of theory) of the title compound is obtained as a solid that melts in air. - 37 - Analysis: Calculated: C 49.22 H 5.59 N 13.51 O 23.14 CI 8.55 Found: C 49.31 H 5.65 N 13.60 CI 8.49 e) Gadolinium complex of 13-chloro-3,6,9-tris(carboxy-methyl) -3,6,9, 15-tetraazabicyclo[9.3. l]pentadeca-1(15) , 11, 13-triene 3.23 g (7.78 mmol) of the title compound from example 5d is dissolved in 20 ml of deionized water and 1.41 g (3.89 mmol) of gadolinium oxide is added. It is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried.

Yield: 4.9 g (100% of theory) of a white amorphous powder, which according to analysis contains 11.9% water. Analysis: Calculated: C 35.88 H 3.54 N 9.85 O 16.87 Cl 6.23 Gd 27.63 Found: C 35.94 H 3.57 N 10.01 Cl 6.17 Gd 27.56 T, relaxivity (L/mmol-sec) , 40°C, 20 MHZ: 5.44 EXAMPLE 6 a) 3,6,9, 15-tetraazabicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene-15-N-oxide 4.5 g (12.9 mmol) of the title compound from example 3b is dissolved in 40 ml of dioxane under nitrogen. 5.8 g (51.7 mmol) of potassium tert . -butylate is added and/it is refluxed overnight. After working up as described in example 3f, 2.61 g (91% of theory) of a slightly yellow oil is obtained which crystallizes when allowed to stand.

Analysis: Calculated: C 59.43 H 8.16 N 25.20 0 7.20 Found: C 59.37 H 8.21 N 25.13 - 38 - b) 3 , 6, 9-tris (carboxymethyl) -3, 6,9, 15-tetraazabicyclo- [9.3. l]pentadeca-l (15) , 11, 13-triene-15-N-oxide 2.4 g (10.77 mmol) of the title compound from example 6a is dissolved in 30 ml of water and 4.1 g (43.4 mmol) of chloroacetic acid is added. It adjusted to pH 9.5 with 6 n potassium hydroxide solution. It is stirred for 12 hours at 45°C and the pH-value is maintained between 9.5-10 with addition of 6 of potassium hydroxide solution. After working up as described in example Id, the crystallization from ethanol/acetone yields 2.7 g (63% of theory) of a strongly hygroscopic powder.

Analysis: Calculated: C 51.51 H 6.10 N 14.14 O 28.26 Found: C 51.63 H 6.01 N 14.08 c) Gadolinium complex of 3, 6, 9-tris (carboxymethyl) -3,6,9, 15-tetraazabicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene-15-N-oxide 2.1 g (5.3 mmol) of the title compound from example i 6b is dissolved in 15 ml of deionized water and 935 mg (2.65 mmol) of gadolinium oxide is added. It is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried.

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

Analysis: Calculated: C 37.08 H 3.84 N 10.18 O 20.34 Gd 28.56 Found: C 37.18 H 3.79 N 10.21 Gd 28.48 - 39 - 91046/2 EXAMPLE 7 a) 3,6, 9-tris (p-tolylsulfonyl ) -3 , 6 , 9-triaza-14-oxa-bicyclo- [9.2.1] tetradeca-1- ( 13 ) , 11-diene A solution of 33 g (200 mmol) of 2 , 5-bis (chloro- methyl) -furan in 700 ml of dimethylformamide is instilled into 121.9 g (200 mmol) of N,N ' ,N"-tris (p-tolylsulfonyl) - diethylenetriamine-N,N"-disodium salt in 1600 ml dimethyl- formamide at 100°C within 3 hours. It is stirred overnight at 100°C. Into the hot solution 2 liters of water is instilled. It is cooled to 0°C. The precipitate is washed with much water and dried in a vacuum (60°C) . After crystallization from acetonitrile 88.14 g (67% of theory) of a white powder is obtained.

Analysis: Calculated: 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 b) 3,6, 9-triaza-14-oxa-bicyclo[9, 2, 1] tetradeca-1 (13) , 11- diene 30 g (45.61 mmol) of the title compound from example 7a is suspended in 500 ml of liquid ammonia at -40°C. Then within 30 minutes, 10.49 g (456.1 mmol) of sodium is added and it is stirred for 3 hours at -40°C. The excess of sodium is destroyed by careful addition of ethanol (discoloration) and ammonia is allowed to evaporate. The residue is taken up with 100 ml of water and is adjusted to pH 11 with 6 n sodium hydroxide solution. Then it is extracted six times with 150 ml of methylene chloride, the organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: acetonitrile/water/32% ammonia solution = 10/3/1) .

Yield: 3.95 g (45% of theory) of a pale yellow oil. - 40 - 91046/2 Analysis : Calculated : C 61.51 H 8.78 N 21.52 O 8.19 Found: C 61.43 H 8.85 N 21.47 c) 3 , 6 , 9-tris (ethoxycarbonylmethyl) -3 , 6, 9-triaza-14-oxa-bicyclo[9.2.1]tetradeca-l(13) , 11-diene 7 ml (62.5 mmol) of bromoacetic acid ethyl ester is slowly instilled at 50°C within 10 minutes into a mixture of 3.7 g (18.95 mmol) of the title compound from example 7b and 6.03 g (56.85 mmol) of anhydrous sodium carbonate in 150 ml of dimethylformamide. It is stirred for 4 hours at 50°C. The solvent is removed in a vacuum and the residue is absorptively precipitated in 200 ml of methylene chloride. It is filtered from the solid and the filtrate is concentrated by evaporation. The remaining oil is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol = 12/1) .

Yield: 6.1 g (71% of theory) of a yellowish oil, which slowly congeals.

Analysis: Calculated: C 58.26 H 7.78 N 9.27 O 24.69 Found: C 58.17 H 7.88 N 9.19 d) Gadolinium complex of 3 , 6 , 9-tris (carboxymethyl) -3 , 6 , 9-triaza-14-oxa-bicyclo[9.2.1]tetradeca-l(13) , 11-diene 5.0 g (11.02 mmol) of the title compound from example 7c is dissolved in 80 ml of ethanol and at 60°C 36 ml of 1 N sodium hydroxide solution is slowly instilled. It is refluxed for 30 minutes. It is evaporated to dryness, taken up with 20 ml of water and is carefully brought to pH 6.5 with 2 N hydrochloric acid. After addition of 2.0 g (5.57 mmol) of gadolinium oxide it is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is first poured - 41 - 91046/2 onto a short cation exchanger column (IR-120) , then it is poured onto a short anion exchanger column (IRA-67) . The water is freeze-dried.

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

Analysis : Calculated: C 36.70 H 3.85 N 8.03 O 21.39 Gd 30.03 Found: C 36.51 H 3.81 N 8.11 Gd 29.91 EXAMPLE 8 Gadolinium complex of 3 , 6 , 9-tris (carboxymethyl) -3 , 6 , 9 , 14-tetraaza-bicyclo- [9.2.1] tetradeca-1 ( 13 ) , 11-diene 10.0 g (22.04 mmol) of the title compound from example 7c is dissolved in 150 ml of ethanol and at 60°C 80 ml of 1 N sodium hydroxide solution is instilled. It is re-fluxed for one hour and then evaporated to dryness. The residue is conveyed into a shaker autoclave and 3.54 g (66.12 mmol) of ammonium chloride is added. After addition of vanadium oxide catalyst (US Patent 2 478 456, Chem.

Abstr. 4_4, 665(1950) 100 ml of ammonia is condensed in. It is heated for 12 hours to 200°C. After evaporation of the ammonia the residue is chromatographed on silica gel (mobile solvent: dioxane/water/32% aqueous ammonia solution = 6/2/1) . Concentration by evaporation yields approximately 5.19 g (56% of theory) of the extremely hygroscopic ammonium salt, which is immediately reacted again. It is dissolved, in 25 ml of deionized water and adjusted to pH 6.5 with 2 N hydrochloric acid. 2.24 g (6.17 mmol) of gadolinium oxide is added and it is stirred for 3 hours at 90°C under nitro-gen. 1 g of activated carbon is added and it is stirred an additional hour at 90°C. The solution is filtered and the filtrate is poured first onto a short cation exchanger - 42 - 91046/3 column (IR-120) , then onto a short anion exchanger column (IRA-67) . The water is removed by freeze-drying.

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

Analysis: Calculated: 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 a) 15-methoxy-3 , 6, 9-tris (p-tolylsulfonyl) -3 , 6, 9-triaza- bicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene 182.85 g (300 mmol) of Ν,Ν' ,NM-tris (p-tolylsulfonyl) -diethylenetriamine-Ν,Ν' ' -disodium salt is dissolved in 2.4 liters of dimethylformamide and heated to 100°C. To it a solution of 88.2 g (300 mmol) of 2 , 6-bis (bromomethyl) - methoxy-benzene in 1 liter of dimethylformamide is instilled within 3 hours. It is stirred overnight at 100°C. Into the hot solution 3 liters of water is instilled and it is cooled to 0°C. The precipitate is washed with much water and dried in a vacuum (60°C) . Crystallization from aceto-nitrile yields 119.3 g (57% of theory) of the title compound as a slightly cream-colored powder.

Analysis: Calculated: C 58.51 H 5.63 N 6.02 O 16.05 S 13.78 Found: C 58.41 H 5.68 N 6.13 S 13.70 b) 15-hydroxy-3 , 6 , 9-triazabicyclo[ 9.3.1] -pentadeca-1(15) ,11, 13-triene 21.75 g (573.2 mmol) of lithium aluminum hydride is carefully added to 100 g (143.3 mmol) of the title compound from example 9a in 2 liters of dibutyl ether and refluxed overnight. It is cooled in an ice bath and excess lithium aluminum hydride is destroyed with ethanol and then with - 43 - 91046/2 water. It is evaporated to dryness, the residue is taken up with 1 liter of 2 N sodium hydroxide solution and is extracted ten times with 200 ml of chloroform. After drying on magnesium sulfate it is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel (mobile solvent: methanol/32% aqueous ammonia solution = 10/1) .

Yield: 8.56 g (27% of theory) of a yellowish oil. Analysis: Calculated: C 65.13 H 8.65 N 18.99 O 7.23 Found: C 65.18 H 8.60 N 19.10 c) 15-hydroxy-3 , 6 , 9-tris ( tert . -butoxycarbonymethyl) -3,6,9-triazabicyclo[9.3.1 ] pentadeca-1 (15) , 11, 13-triene 8.3 g (37.50 mmol) of the title compound from example 9b is dissolved in 250 ml of dimethylformamide and 15.55 g (112.5 mmol) of anhydrous potassium carbonate is added. To this 16.3 ml (112.5 mmol) of bromoacetic acid tert. -butyl ester is instilled within 30 minutes and is stirred overnight at room temperature. The solvent is evaporated to dryness, it is taken up with 300 ml of water and extracted three times with 150 ml of methylene chloride. The organic phases are dried on magnesium sulfate and concentrated by evaporation in a vacuum. The remaining oil is chromatographed on silica gel (mobile solvent: methylene chloride/-methanol = 15/1) .

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

Analysis : Calculated: C 63.91 H 8.75 N 7.45 O 19.87 Found: C 63.83 H 8.85 N 7.49 - 44 - d) 15-hydroxy-3 , 6 , 9-tris- (carboxymethyl) -3,6,9, -triaza-bicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene 13.0 g (23.06 mmol) of the title compound from example 9c is dissolved in 150 ml of trifluoroacetic acid and stirred overnight at room temperature. It is concentrated by evaporation in a vacuum. The residue is taken up with a little water and is purified on ion exchangers as described in example Id. Crystallization from methanol/acetone yields 6.5 g (71% of theory) of the title compound as a powder that melts in the air.

Analysis: Calculated: C 54.67 H 6.37 N 10.63 0 28.33 Found: C 54.51 H 6.30 N 10.57 e) Gadolinium complex of 15-hydroxy-3 , 6 , 9-tris (carboxymethyl) -3 , 6,9-triazabicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene 4.0 g (10.1 mmol) of the title compound from example 9d is dissolved in 25 ml of deionized water and 1.84 g (5.05 jmmol) of gadolinium oxide is added. It is stirred for 3 hours at 90°C, 1 g of activated carbon is added and it is stirred an additional hour at this temperature. The solution is filtered and the filtrate is freeze-dried. 6.04 g (96% of theory) of an amorphous powder is obtained, which according to analysis contains 13.5% water.

Analysis: Calculated: C 39.33 H 4.04 N 7.65 O 20.38 Gd 28.61 Found: C 39.41 H 4.10 N 7.58 Gd 28.51 EXAMPLE 10 a) 6-benzyl-3 , 9-bis (p-tolylsulfonyl) -3 ,6,9, 15-tetraaza-bicyclo [9.3.1] -pentadeca-1 (15) , 11 , 13-triene A solution of 35.2 g (200 mmol) of 2,6 bis(chloro-methyl ) pyridine (dissolved in 700 ml of dimethylformamide) is instilled into 109.12 g (200 mmol) of Ν,Ν· ' -bis (p-tolyl-sulfonyl) -N* -benzyl-diethylenetriamine-N-N"-disodium salt in 1500 ml of dimethylformamide, at 100°C within 3 hours. It continues to be stirred overnight at 100°C. Into the hot solution 2 liters of water is instilled and it is cooled to 0°C. The precipitate is washed with water several times and dried in a vacuum (60°C) . Crystallization from aceto-nitrile/ ether yields 78.5 g (65% of theory) of a cream-colored powder.

Analysis: Calculated: C 63.55 H 6.00 N 9.25 O 10.58 S 10.60 Found: C 63.48 H 5.94 N 9.18 S 10.63 b) 6-benzyl-3 ,6,9, 15-tetraazabicyclo[9.3. l]pentadeca-,1(15) ,11,13-triene 9.41 g (248 mmol) of lithium aluminum hydride is carefully added to 75 g (124 mmol) of the title compound from example 10a in 1.5 liters of dibutyl ether, and it is refluxed overnight. After cooling in an ice bath the excess lithium aluminum hydride is destroyed with ethanol and water. It is evaporated to dryness, taken up with 500 ml of water and adjusted to pH 11 with 6 n potassium hydroxide solution. It is extracted six times with 100 ml of chloroform, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography on silica gel (mobile solvent: ethanol/32% aqueous ammonia solution = 12/1) yields 22.4 g (61% of theory) of a yellowish oil, which congeals in a glassy manner. - 46 9104|6/2 Analysis : Calculated : C 72.94 H 8.16 N 18.90 Found: C 72.75 H 8.23 N 18.81 c) 6-benzyl-3 , 9-bis (ethoxycarbonylmethyl) -3,6,9, 15-tetra-azabicyclo[9.3.1 ] entadeca-1 (15) , 11, 13-triene 10 g (33.74 mmol) of the title compound from example 10b is dissolved in 300 ml of dimethylformamide . 7.13 g (67.48 mol) of anhydrous sodium carbonate is added and it is heated to 50°C. Then within 15 minutes 8.3 ml (74.2 mmol) of bromoacetic acid ethyl ester is instilled and it continues to be stirred overnight at 50°C. The solvent is evaporated in a vacuum, the residue is absorptively precipitated twice with 350 ml of methylene chloride, filtered and concentrated by evaporation. The remaining oil is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol = 10/1) .

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

Analysis : Calculated: C 66.64 H 7.74 N 11.96 O 13.66 Found: C 66.51 H 7.81 N 11.88 d) 3 , 9-bis (carboxymethyl) -3,6,9, 15-tetraazabicyclo [ 9.3.1]-pentadeca-1 ( 15) , 11 , 13-triene 12 g (25.6 mmol) of the title compound from example 10c is dissolved in 100 ml of ethanol and heated to 60°C. To this solution 32 ml of 2 N sodium hydroxide solution is instilled and it is refluxed for one hour. It is evaporated to dryness and the residue is dissolved in 200 ml of 5% acetic acid. It is hydrogenated on Pd/C. After hydrogen absorption is finished, it is filtered from the catalyst, concentrated by evaporation in a vacuum and purified as - 47 - 91046/2 described in example Id on ion exchangers. Crystallization from ethanol/acetone yields 6.52 g (79% of theory) of a strongly hygroscopic solid.

Analysis: Calculated: C 55.88 H 6.88 N 17.38 O 19.85 Found: C 55.79 H 6.94 N 17.27 e) Manganese (II) complex of 3 , 9-bis (carboxymethyl) - 3,6,9, 15-tetraazabicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene 4 g (12.4 mmol) of the title compound from example lOd is dissolved in 20 ml of deionized water and 1.43 g (12.4 mmol) of manganese (II) carbonate is added. It is heated for 2 hours to 80°C. The solution is first poured onto a short cation exchanaer column (IR-120) . then onto a short anion exchanger column (IRA-67) . The eluate (water) is refluxed with 1 g of activated carbon for an hour and filtered. The filtrate is freeze-dried. 4.4 g (87% of theory) of a slightly pink shiny amorphous powder is obtained.

(Analysis: Calculated: C 48.00 H 5.37 N 14.93 O 17.05 Mn 14.64 Found: C 47.93 H 5.41 N 14.87 Mn 14.58 EXAMPLE 11 a) 3 , 6-bis- (p-tolylsulfonyl) -3,6, 12-triazabicyclo[6.3^1]-dodeca-l(12) ,8,10-triehe A solution of 35.2 g (0.2 mol) of 2 , 6-bis (chloro-methyl) -pyridine (dissolved in 700 ml of dimethylformamide) is instilled into 82.48 g (0.2 mol) of N, · -bis (p-tolylsulfonyl) -ethylenedia ine-di-sodium salt in 1600 ml of dimethylformamide, at 100°C within 3 hours. It continues to be stirred overnight at 110°C. Into the hot solution 2 liters of water is instilled, the precipitate is suctioned - 48 - off and washed with much water. After drying in a vacuum (60°C) it is recrystallized from acetonitrile.

Yield: 67.9 g (72% of theory) of a cream-colored powder. ! ' Analysis: Calculated: C 58.58 H 5.34 N 8.91 0 13.57 S 13.60 Found: C 58.41 H 5.37 N 8.85 S 13.'53 b) 3,6, l2-triazabicyclo[6.3. l]dodeca-l (12) , 8, 10-triene trihydrosulfate < 67.0 g (142 mmol) of the title compound from example 11a is added to 200 ml of concentrated sulfuric acid and stirred for 48 hours at 100°C. It is cooled to 0°C and 1 liter of absolute ether is instilled. The precipitate is suctioned off and is absorptively precipitated in 600 ml of methanol. It is filtered and then evaporated to dryness. Drying in a vacuum (60°C) yields 44.17 g (68% of theory) of the title compound as crystalline solid.

Analysis: I Calculated: C 23.63 H 4.19 N 9.19 0 41.97 S 21.Ί 03 Found: C 23.57 H 4.24 N 9.11 S 20.96 c) 3,6,12-triazabicyclo[6.3.1]dodeca-l(12) ,8, 10-triene 42.0 g (91.8 mmol) of the title compound from exampL lib is dissolved in 100 ml of water and adjusted to pH 11 with 32% sodium hydroxide solution. It is extracted six times with 200 ml of methylene chloride and the combined phases are dried on magnesium sulfate. After concentration by evaporation in a vacuum, 11.24 g (75% of theory) of a slightly yellow oil is obtained.

Analysis: Calculated: C 66.23 H 8.03 N 25.74 Found: C 66.17 H 8.09 N 25.67 - 49 - 91046/2 d) 3 , 6-bis (carboxymethyl) -3,6, 12-triazabicyclo[6.3.1]- dodeca-l(12) ,8, 10-triene 10 g (61.27 mmol) of the title compound from example 11c is dissolved in 100 ml of water and 17.37 g (183.8 mmol) of chloroacetic acid is added. It is adjusted to pH 9.5 by addition of 6 n potassium hydroxide solution and heated to 45°C. It is stirred at this temperature for 12 hours, and the pH is maintained between 9.5 - 10 by addition of 6 n potassium hydroxide solution. It is cooled and purified as described in example Id on ion exchangers. Crystallization from ethanol/acetone yields 11.47 g (67% of theory) of the title compound as crystalline solid.

Analysis: Calculated: 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-triazabicyclo [6.3.1] dodeca-1 ( 12 ) , 8 , 10-triene ( 10.0 g (35.8 mmol) of the title compound from example lid is dissolved in 40 ml of deionized water and 4.12 g (35.8 mmol) of manganese (II) carbonate is added. It is stirred for 2 hours at 80°C. The solution is poured onto a short anion and cation exchanger column and the eluate (water) is stirred with 1 g of activated carbon for 1 hour at 80°C. It is filtered and the filtrate is freeze-dried.

Yield: 12.7 g (96% of theory) of the title compound as amorphous powder, which according to analysis contains 11.3% water.

Analysis: Calculated: 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 Production of a solution of gadolinium complex of 3,6,9-tris (carboxymethyl) -3 ,6,9, 15-tetraazabicyclo[9.3. l]penta-deca-l(15) , 11 , 13-triene 534.63 g (1 ol) of the compound described in example le was dissolved in 1200 ml of water pro injectione (p.i.). After addition of 24.62 g (50 mmol) of monohydrate of calcium trisodium salt of DTPA, CaNa3DTPA, it is filled with water p.i. up to 2000 ml. The solution is then ultra-, filtered, put into ampules and sterilized by heat and is ready for use for parenteral application.

EXAMPLE 13 Production of a solution of the meglumine salt of manganese (II) complex of 3, 6, 9-tris (carboxymethyl) -3,6,9 ,15-tetraaza-bicyclo [ 9.3.1 ] pentadeca-1 ( 15) , 11 , 13-triene 34.92 g (50 mmol) of the compound described in example lh (water content 12.29%) is dissolved in 65 ml of water (p.i.). After addition of 492 mg (lmmol) of mono-hydrate of the calcium trisodium salt of DTPA, CaNa3DTPA, it (is filled with water p.i. to 100 ml. The solution is finally ultrafiltered, put into ampules and sterilized by heat and is ready for use for parenteral application.

EXAMPLE 14 Composition of a powder for the production of a suspension for oral application. 4.000 g of the gadolinium complex described in example le 3.895 g of annitol 0.100 g of polyoxyethylenepolyoxypropylene polymer 0.005 g of aromatic substances 8.000 g ! - 51 - 91046/2 EXAMPLE 15 Production of a solution of indium (III) complex of 3,6,9-tris (carboxymethyl) -3,6,9, 15-tetraazabicyclo [9.3.1] penta-decane A solution of 100 micrograms of the compound i described in example 2a in 5 ml of a mixture of a 150 immolar sodium chloride and a 150 mmolar sodium acetate solution (pH 5.8) is mixed with a solution of 5 ml of indium(III) chloride in 1 ml of N-hydrochloric acid. It is brought to pH 7.2 by addition of 0.1 N-sodium hydroxide solution,! the sterilely filtered solution is filled into multivials and lyophilized. The residue is taken up in physiological saline solution and then represents a preparation suitable for radiodiagnosis . | In a similar way a preparation suitable for radiotherapy is obtained with yttrium 90 chloride.

EXAMPLE 16 a) 3,6, 9-tris (p-tolylsulfonyl) -14-oxa-3 , 6 , 9-triazabicyclo- [9.2.1] tetradecane 39.01 g (64 mmol) of N, N 1 , N"-tris (p-tolylsulfonyl ) -diethylenetriamine-N, N"-disodium salt dissolved in 210| ml of dimethylformamide is instilled into a solution of 28.19 g (64 mmol) of 2 , 5-bis (p-tosyloxymethyl) -tetrahydrofuran in 500 ml of dimethylformamide within 2 hours at 100°C and is stirred for 5 hours at 120°C. Into the hot solution 700 ml of water is instilled and it is cooled to 0°C. The precipitate is suctioned off, washed with water and dried in a vacuum at 50°C. After recrystallization from acetone 33.5 g of the title compound is obtained as white powder, melting point 175 - 178°C. - 52 - 91046/2 Analysis: Calculated: C 56.26 H 5.94 N 6.35 S 14.53 Found: C 56.01 H 5.99 N 6.28 S 14.29 b) 14-oxa-3 , 6, 9-triazabicyclo[9.2. l] tetradecane 30 g (45.3 mmol) of the title compound from example 16a is added into 90 ml of concentrated sulfuric acid and stirred for 24 hours at 90°C. It is then cooled to 0°C and 350 ml of dry ether is instilled. The precipitate formed is suctioned off and is dissolved in 50 ml of 40% sodium hydroxide solution and the solution is extracted 10 times with 50 ml of dichloromethane each. The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum. 6.23 g (69% of theory) of the title compound is obtained as white powder.

Analysis: Calculated: C 60.27 H 10.62 N 21.08 Found: C 60.03 H 10.75 N 20.95 c) 3 , 6, 9-tris- (carboxymethyl) -14-oxa-3 , 6, 9, - triazabi- ' cyclo [9.2.1] tetradecane 6 g (30.1 mmol) of the title compound from example 16 b is dissolved in 35 ml of water, mixed with 11.38 g (120.4 mmol) of chloroacetic acid and this solution is adjusted to pH 9.5 with 6N potassium hydroxide solution. It is heated for 12 hours to 45°C and during this time the pH is maintained at 9.5 - 10 by addition of more potassium hydroxide solution. Then it is cooled to room temperature, mixed slowly with concentrated hydrochloric acid until reaching pH 2 and then concentrated by evaporation in a vacuum. The residue is dissolved in 100 ml of water and this solution is poured onto a cation exchanger column (IR 120) . First the column is washed with much water. Then the desired sub- - 53 - 91046/2 stance is eluted with 0.5 N ammonia solution, the solution is concentrated by evaporation, the residue is dissolved in 100 ml of water and the solution is poured onto a anion exchanger column (IRA 67) . First of all it is washed with water, then it is eluted with 0.5 N formic acid. The acid fractions are concentrated by evaporation, the residue is dissolved in methanol. After addition of acetone, the1 title compound (5.74 g, 51% of theory) crystallizes out.

Analysis: Calculated: C 51.47 H 7.29 N 11.25 Found: C 51.60 H 7.21 N 11.38 ' d) Gadolinium complex of 3 , 6 , 9-tris- (carboxymethyl) -14 oxa-3,6, 9-triazabicyclo [9.2.1] etradecane 3.73 g (10 mmol) of the title compound from example 16c is dissolved in 15 ml of water and stirred for 3 hours with 1.81 g (5 mmol) of gadolinium oxide at 80°C. The solution obtained is filtered and successively absorptively-precipitated with 0.5 g of cation exchanger (IR 120) and 0.5 (g of anion exchanger (IRA 67) , the solution is again filtered and subjected to freeze-drying. 5.07 g (91% of i theory) of the title compound is obtained as white amorphous power with a water content of 5.4%.

Analysis: ! Calculated: C 36.42 H 4.59 N 7.96 Gd 29.80 Found: C 36.30 H 4.61 N 7.82 Gd 29.59 (water content taken into account) EXAMPLE 17 a) 3,6, 9-tris (p-tolylsulfonyl) -14-thia-3 , 6 , 9-triazabicyclo- [9.2. l]tetradeca-l(13) , 11-diene 60.97 g (100 mmol) of N , ' , " -t is (p-tolylsulfonyl ) -diethylenetriamine-N, N"-disodium salt is dissolved in 800 ml 54 - of dimethylformamide and 19.9 g (110 mmol) of 2,5-bis-chloromethylthiophene, dissolved in 330 ml of dimethyl-formamide, is instilled at 50°C within 90 minutes. It is stirred another 90 minutes at 50°C, then 1 liter of water is instilled and the precipitate formed is suctioned off,: it is washed with water and the residue is dried at 50°C in a vacuum drying chamber and recrystallized from dioxane. 47.1 g (70% of theory) of the title compound is obtained as a light yellow powder, melting point 265 - 268°C.

Analysis: Calculated: C 55.25 H 5.24 N 6.24 S 19.03 Found: C 55.38 H 5.44 N 6.10 S 19.01 b) 14-thia-3 , 6 , 9-triazabicyclo [9.2.1] tetradeca-1 (13 ) , 11-diene 45 g (66.8 mmol) of the title compound from example 17a is added to 130 ml of concentrated sulfuric acid and stirred for 24 hours at 90 - 95°C. After cooling to 0°C, 500 ml of ether is instilled, it is suctioned off from the precipitate formed and the precipitate is dissolved in 70 ml of 40% sodium hydroxide solution. The solution is extracted five times with' 100 ml of dichloromethane each time, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is recrystallized from ether/hexane (3:1) and 7.8 g (55% of theory) of the title compound is obtained as white powder.

Analysis: Calculated: C 56.83 H 8.11 N 19.88 S 15.17 Found: C 56.59 H 8.02 N 20.12 S 15.00 c) 3,6, 9-tris- (carboxymethyl) -14-thia-3 , 6 , 9-triazabicyclo-[9.2.1] tetradeca-1 ( 13 ) , 11-diene 7.5 g (35.5 mmol) of the title compound from example 17b is dissolved in 45 ml of water, mixed with 13.42 g (142 mmol) of chloroacetic acid and the pH is adjusted to 9.5 with 6 N potassium hydroxide solution. Then it is heated for 12 hours to 45 - 50°C and the pH is maintained at 9.5 -10 by addition of more potassium hydroxide solution. After cooling to 10°C it is mixed with concentrated hydrochloric acid until reaching pH 2. The precipitate thus formed is isolated by suctioning off, it is dissolved in 100 ml of water and the solution is adsorbed on a cation exchanger column (IR 120) , the column is washed with 2 1 of water, then with 0.5 N ammonia solution. The ammonia fraction is concentrated by evaporation in a vacuum, the residue is dissolved in 100 ml of water and the solution is bonded on an anion exchanger (IRA 67) . The exchanger column is eluted with water and 0.5 N formic acid. From the acid fraction the title compound is obtained by concentration by evaporation in a vacuum. For additional purification methanol is dissolved and precisely enough acetone is added until a precipitate forms. It is cooled to 0°C, it is suctioned off from the precipitate and 7.7 g (56.3% of theory) of the title compound is obtained as light yellow powder.

Analysis: Calculated: C 49.86 H 6.01 N 10.90 S 8.32 Found: C 49.71 H 5.85 N 10.80 S 8.07 d) Gadolinium complex of 3, 6, 9-tris- (carboxymethyl) -14-thia-3 , 6, 9-triazabicyclo[9.2.1] tetradeca-1 (13) , 11-diene 2 g (5.19 mmol) of the title compound from example 17c is heated with 941 mg (2.60 mmol) of gadolinium oxide in 20 ml of water for 4 hours to 85 - 90°C. The solution ob- tained is filtered and successively absorptively precipitated with 0.26 g of cation exchanger (IR 120) and 0.25 g of anion exchanger (IRA 67) , the solution is again filtered and freeze-dried. 2.66 g (95% of theory) of the title compound is obtained as white amorphous power, water content 5.7%. Analysis: Calculated: C 35.61 H 3.74 Gd 29.14 N 7.79 S 5.94 Found: C 35.50 H 3.51 Gd 29.02 N 7.98 S 6.18 (water content taken into account in the calculation) , EXAMPLE 18 a) 13-methoxy-3 , 6 , 9-tris (p-tolylsulfonyl) -3,6,9, 15-tetra-azabicyclo[9.2.1] -pentadeca-1 (15) , 11, 13-triene 60.97 g (100 mmol) of Ν,Ν' ,N"-tris (p-tolylsulfonyl) -diethylenetriamine-N,N"-disodium salt is dissolved in 800 ml of dimethylfor amide and 47.76 g (100 mmol) of 2.6-bis-(p-tolylsulfonyloxymethyl) -4- ethoxy-pyridine, dissolved in 400 ml of dimethylformamide, is instilled at 50°C within 90. minutes. It is stirred for 5 hours more at 90°C, then 1.1 liter of water is instilled, the precipitate formed is suctioned off, Washed with water, the product is dried in a vacuum shelf dryer and recrystallized from isopropyl alcohol. 43.3 g (62% of theory) of the title compound is obtained as white powder.

Analysis: Calculated: C 56.71 H 5.48 N 8.016 S 13.76 Found: C 56.90 H 5.31 N 8.00 S 13.59 b) l3-methoxy-3 , 6 , 9, 15-tetraazabicyclo[9.3. l]pentadeca-1(15) ,11, 13-triene 30 g (42.9 mmol) of the title compound from example 18a is stirred with 100 ml of concentrated sulfuric acid for 24 hours at 95 °C. After cooling to 0°C, 400 ml of ether is instilled, it is suctioned from the precipitate formed and dissolved in 60 ml of 40% sodium hydroxide solution. The solution is extracted five times with 75 ml of dichloro- ethane each, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is recrystallized from diisopropyl ether and 6.59 g (65% of theory) of the title compound is obtained as white powder.

Analysis: Calculated: C 60.99 H 8.53 N 23.71 Found: C 61.15 H 8.40 N 23.52 c) 13-methoxy-3 , 6 , 9-tris- (carboxymethyl) -3 ,6,9, 15-tetraaza-bicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene 6.2 g (26.2 mmol) of the title compound from example "18b is dissolved in 40 ml of water, mixed with 9.90 g (104.8 mmol) of chloroacetic acid. By addition of 6N potassium hydroxide solution a pH of 9.5 is adjusted and it is heated for 8 hours to 45 - 50°C. During this time the pH is maintained at 9.5 - 10 by addition of further potassium hydroxide solution. It is then cooled in an ice bath, mixed with concentrated hydrochloric acid up to a pH of 2. A precipitate is formed, suctioned off, the residue is dissolved in 80 ml of water under low heat and the solution is adsorbed on a cation exchanger column (IR 120) . The column is first eluted with abundant water, then with 0.5 N ammonia solution. The basic eluate is gathered and concentrated by evaporation in a vacuum. The residue is dissolved in 80 ml of water and the solution is adsorbed on an anion exchanger column (IRA 67) . At first it is eluted with water, then with 0.5 N formic acid. The acid fraction is concentrated by evaporation in a vacuum, the residue is dissolved in methanol and by addition of acetone the title compound - 58 - precipitates. 7.42 g (69% of theory) is obtained as white powder.

Analysis: Calculated: C 52.68 H 6.39 N 13.65 Found: C 52.81 H 6.22 N 13.80 d) Gadolinium complex of 13-methoxy-3,6,9-tris(carboxy- ethyl) -3 , 6 , 9 , 15-tetraazabicyclo [9.3.1]pentadeca-1(15) ,11, 13-triene 5 g (12.18 mmol) of the title compound from example 18c is heated with 2.21 g (6.09 mmol) of gadolinium oxide in 60 ml of water for 4 hours to 85 - 90°C. The solution is filtered and freeze-dried. 6.74 g (98% of theory) of the title compound is obtained as white amorphous powder. Water content 4.7%.

Analysis: Calculated: C 38.29 H 4.10 Gd 27.85 N 9.92 Found: C 38.41 H 3.92 Gd 27.60 N 9.99 (water content taken into account in the calculation) I : EXAMPLE 19 a) 13-chloro-3v, 6, 9-tris- (tert. -butoxycarbonylmethyl) -3,6,9, 15-tetraazabicyclo [9.3. l]pentadeca-l (15) , 11, 13-triene 18.72 g (95.96 mmol) of bromoacetic acid-tert. -butyl-ester is added to 7 g (29.08 mmol) of the title compound from example 5c and 10.17 g (95.96 mmol) of sodium carbonate in 200 ml of acetonitrile, and is stirred for 24 hours at room temperature.

It is concentrated by evaporation in a vacuum, the residue is taken up with 300 ml of water and is extracted three times with 200 ml of methylene chloride. After drying of the organic phases on magnesium sulfate, it is concentrated by evaporation in a vacuum and the remaining oil is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol = 15/1) .

Yield: 14.08 g (83% of theory) of a colorless oil. Analysis: Calculated: C 59.73 H 8.12 N 9.61 0 16.46 Cl 6.08 Found: C 59.67 H 8.25 N 9.58 Cl 6.01 b) 13- (N-pyrrolidino) -3 , 6, 9-tris- (tert. -butoxycarboxym-ethyl) -3,6,9, 15-tetraazabicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene 1.11 g (46.3 mmol) of sodium hydride (previously washed with pentane) is carefully added to 13.5 g (23.15 mmol) of the title compound from example 19a and 3.94 g (46.3 mmol) of pyrrolidinone and 612 mg (2.32 mmol) of 18-crown-6 in 200 ml of anhydrous dimethylformamide. It is stirred for 72 hours at 70°C under nitrogen. The solution is cooled to room temperature and poured into 1.2 1 of ice water. Then it is extracted three times with 250 ml of ethyl acetate. The organic phase is dried on magnesium (sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/methanol : 13/1).

Yield: 5.7 g (39% of theory) of a colorless oil, which crystallizes when allowed to stand.

Analysis: Calculated: C 62.73 H 8.45 N 11.09 O 17.73 Found: C 63.68 H 8.54 N 11.01 c) 13- (N-pyrrolidino) -3 , 6, 9-tris- (carboxymethyl) -3 ,6,9, 15-tetraazabicyclo[9.3.1]pentadeca-l(15) , 11, 13-triene 5.1 g (8.07 mmol) of the title compound from example 19b is dissolved in 50 ml of trifluoroacetic acid; and stirred for 6 hours at room temperature. The solvent is - 60 - 91046/2 removed in a vacuum and is purified, as described in example, Id on an anion exchanger.

Crystallization from MeOH/acetone yields 2.88 g (77% of theory) of a strongly hygroscopic substance.

Analysis: Calculated: C 54.42 H 6.31 N 15.11 O 24.17 Found: C 54.37 H 6.42 N 15.05 d) Gadolinium complex of 13- (N-pyrrolidino) -3 , 6, 9-tris- (carboxymethyl) -3 , 6 , 9 , 15-tetraazabicyclo[9.3.1] pentadeca- 1(15) ,11, 13-triene 2.5 g (5.4 mmol) of the title compound from example 19c is dissolved in 20 ml of deionized water and 978 mg (2.7 mmol) of gadolinium oxide is added. It is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried.

Yield: 3.32 g (100% of theory) of an amorphous powder, which according to analysis contains 13.2% water. Analysis: Calculated: C 40.83 H 4.24 N 11.34 O 18.13 Gd 25.46 Found: C 40.74 H 4.37 N 11.28 Gd 25.41 EXAMPLE 20 a) l3-azido-3,6,9-tris-(tert.-butoxycarbonylmethyl)- ; 3,6,9, 15-tetraazabicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene 21 g (36.01 mmol) of the title compound from example 19a is dissolved in 200 ml of dimethylformamide and 7.02 g (108 mmol) of sodium azide as well as 951 mg (3.6 mmol)' 18-crown-6 is added. It is stirred for 24 hours at 90°C. , After cooling to room temperature it is poured into .5 1 of ice water and extracted three times with 200 ml of ethyl acetate. After drying of the organic phase on magnesium sulfate, it is concentrated by evaporation and the i remaining oil is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol = 15/1) . 1 Yield: 10.83 g (51% of theory) of a pale yellow oil. Analysis: I Calculated: C 59.06 H 8.03 N 16.63 O 16.28 Found: C 59.17 H 8.05 N 16.51 b) 13- amino-3,6,9-tris-(tert.-butoxycarboxymethyl)- · 3,6,9, 15-tetraazabicyclo[9.3.1]pentadeca-l(15) , 11 , 13-triene 10 g (16.96 mmol) of the title compound from example 20a is dissolved in 400 ml of ethanol and 1 g of Pearlman catalyst (20% palladium hydroxide on carbon) is added.: After 24 hour hydrogenation at normal pressure the catalyst is suctioned off and concentrated by evaporation in a ' vacuum. The remaining oil is chromatographed on silica gel (mobile solvent: methylene chloride/methanol/triethylamine = 10/1/0.05). 8.89 g (93% of theory) of a slightly yellowish oil is obtained.

Analysis: Calculated: C 61.78 H 8.76 N 12.42 0 17.03 ! Found: C 61.67 H 8.91 N 12.35 j v, I . c) 13-amino-3,6,9-tris-(carboxymethyl)-3,6,9,15-tetraaza-bicyclo [ 9.3.1] entadeca-1 ( 15) , 11 , 13-triene 8.2 g (14.55 mmol) of the title compound from example 20b is dissolved in 100 ml of trifluoroacetic acid and stirred for 6 hours at room temperature. After evaporation of the solvent in a vacuum the residue is dissolved in 100 ml of water and poured onto a column filled with poly (4-vinyl-pyridine) . After concentration by evaporation in a vacuum and crystallization from methanol/acetone, 5.24 g (91% of theory) of a strongly hygroscopic solid is obtained. - 62 - 91046/2 Analysis: Calculated: C 51.64 H 6.37 N 17.71 O 24.28 Found: C 51.74 H 6.31 N 17.63 d) Gadolinium complex of 13-amino-3 , 6, 9-tris- (carboxy- methyl) -3 , 6, 9, 15-tetraazabicyclo[9.3. l]pentadeca- 1(15) , 11, 13-triene 4.8 g (12.14 mmol) of the title compound from example 20c is dissolved in 35 ml of deionized water and 2.2 g (6.07 mmol) of gadolinium oxide is added. It is stirred for 3 hours at 90°C and the pH is maintained at 5.5 by addition of acetic acid. The solution is filtered and poured onto a column filled with poly (4-vinyl-pyridine) . After treatment with activated carbon it is again filtered and freeze-dried.

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

Analysis: Calculated: C 37.15 H 4.06 N 12.74 O 17.47 Gd 28.61 Found: C 37.08 H 4.17 N 12.68 Gd 28.54 EXAMPLE 21 a) 13- (hydroxyacetamido) -3 , 6, 9-tris- (tert. -butoxycarbonyl-methy1) -3 , 6 , 9 , 15-tetraazabicyclo [9.3.1] pentadeca-1(15) ,11, 13-triene 5.8 g (10.28 mmol) of the title compound from example 20b, 861 mg (11.32 mmol) of glycolic acid and 1.53 g (11.32 mmol) of 1-hydroxy-lH-benzotriazole hydrate are dissolved in 20 ml of absolute dimethylformamide and cooled to 0°C. 2.36 g (11.32 mmol) of dicyclohexylcarbodiimide is added and it is stirred for 1 hour at 0°C , then overnight at room temperature. The solution is poured into 150 ml of ice water and extracted three times with 150 ml of ethyl acetate. After drying of the organic phase on magnesium sulfate, it is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/methanol = 10/1) .

Yield: 2.88 g (45% of theory) of a colorless solid. Analysis: Calculated: C 59.88 H 8.27 N 11.26 O 20.59 Found: C 59.76 H 8.35 N 11.31 b) 13- (hydroxyacetamido) -3 , 6, 9-tris- (carboxymethyl) -3,6,9, 15-tetraazabicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene 2.7 g (4.34 mmol) of the title compound from example 21a is dissolved in 40 ml of trifluoroacetic acid and stirred for 6 hours at room temperature. It is concentrated by evaporation in a vacuum and the residue is purified as described in example Id on an anion exchanger.

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

Analysis: Calculated: C 50.32 H 6.00 N 15.45 O 28.23 ,Found: C 50.24 H 6.07 N 15.49 c) Gadolinium complex of 13- (hydroxyacetamido) -3,6, 9-tris- (carboxymethyl) -3,6,9, 15-tetraazabicyclo[9.3. l]pentadeca-1(15) ,11, 13-triene 1.45 g (3.2 mmol) of the title compound from example 21 b is dissolved in 10 ml of deionized water and 580 mg (1.6 mmol) of gadolinium oxide is added. It is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried.

Yield: 1.94 g (100% of theory) of an amorphous powder, which according to analysis contains 11.5% water. - 64 - Analysis: ; Calculated: C 37.55 H 3.98 N 11.53 O 21.06 Gd 25.88 Found: C 37.48 H 4.11 N 11.48 Gd 25.79 EXAMPLE 22 a) 13-chloro-3 , 6, 9-tris- (p-tolylsulfonyl) -3 , 6, 9-triazabi-cyclo[9.3. l]pentadeca-l (15) , 11, 13-triene 182.85 g (300 mmol) of Ν,Ν' ,N"-tris (p-tolylsulfonyl) -diethylenetriamine-N Nl,-disodium salt is dissolved in 2.4 1 of dimethylformamide and heated to 100°C. To this a solution of 63.15 g (300 mmol) of 4-chloro-2 , 6-bis (chloromethl) -pyridine in 1 liter of dimethylformamide is instilled. It is stirred overnight at 100°C. ..; Into the still hot solution 3 1 of water is instilled and it is cooled to room temperature. The precipitate is washed with much water and dried in a vacuum (60°C) .

Crystallization from acetonitrile yields 128.7 g (61% of theory) of the title compound as a colorless powder.

Analysis: ,Calculated: i C 54.65 H 5.02 N 7.97 O 13.65 S 13.68 Cl 5.04 Found: C 54.61 H 5.13 N 7.91 S 13.65 Cl 5.09 b) 13- (N-morpholino) -3 , 6, 9-tris- (p-tolylsulfonyl) -3,6,9-triazabicyclo[9.3. l]pentadeca-l (15) , 11, 13-triene 126 g (179 mmol) of the title compound from example 22a is dissolved in 500 ml of dimethyl sulfoxide and 87.12 g (1 mol) of morpholine is added. The solution is stirred in an autoclave for 48 hours at 140°C and 10 bars. It is cooled off, poured on 3 liters of ice water and the precipitate is suctioned off. After drying in a vacuum at 60°C, it is recrystallized from acetone. 87.72 g .(65% of theory) is obtained as cream-colored powder. - 65 - 91046/2 I Analysis: Calculated: C 57.32 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 I c) 13- (N-morpholino) -3 , 6, 9 , 15-tetraazabicyclo [ 9.3. l]penta-deca-1 (15) , 11, 13-triene I 86 g (114 mmol) of the title compound from example 22b is added into 270 ml of concentrated sulfuric acid and stirred for 48 hours at 100°C. It is cooled to 0°C and 1.35 1 of absolute ether is instilled. The precipitate is ;suc-tioned off and suspended in 100 ml of aqueous sodium hydroxide solution (pH 12) . It is extracted 7 times with 150 ml of chloroform and the combined organic phases are dried on magnesium sulfate. After concentration by evaporation in a vacuum 22.26 g (67% of theory) of a yellowish oil is obtained, which crystallizes when allowed to stand.

Analysis: Calculated: C 61.82 H 8.65 N 24.04 O 5.49 ; Found: C 61.89 H 8.59 N 24.13 d) 13- (N-morpholino) -3 , 6 , 9-tris- (carboxymethyl) -3 , 6 , 9 , 15-tetraazabicyclo[9.3. l]pentadeca-l (15) , 11 , 13-triene 10 g (34.3 mmol) of the title compound from example i 22c is dissolved in 150 ml of water and 12.85 g (136 mmol) of chloroacetic acid is added. It is adjusted to pH 9.5 with 6 N potassium hydroxide solution. It is stirred! for 12 hours at 45°C and the pH is maintained between 9.5 - 10 by addition of 6 N potassium hydroxide solution. It is adjusted to pH 2 with concentrated hydrochloric acid and is purified on ion exchangers as described in example ld Crystallization from methanol/acetone yields 9.9 g (62% of theory) of the title compound as a strongly hygroscopic solid. ! - 66 - 91046/2 Analysis: Calculated: C 54.18 H 6.71 N 15.05 O 24.06 Found : C 54.09 H 6.82 N 15.01 e) Gadolinium complex of 13- (N-morpholino) -3 , 6 , 9-tris-(carboxymethyl) -3,6,9, 15-tetraazabicyclo [9.3. l]pentadeca-1 (15) , 11, 13-triene 9 g (19.33 mmol) of the title compound from example 22d is dissolved in 60 ml of deionized water and 3.5 g (9.67 mmol) of gadolinium oxide is added. It is stirred for 3 hours at 90°C and the pH is maintained at 5.5 by addition of acetic acid. The solution is filtered and poured onto a column filled with poly) 4-vinyl-pyridine) . After treatment with activated carbon it is again filtered and freeze-dried.

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

Analysis: Calculated: C 40.70 H 4.55 N 11.30 O 18.07 Gd 25.37 Found: C 40.63 H 4.64 N 11.25 Gd 25.28 EXAMPLE 23 a) 13-chloro-3 , 6 , 9-tris- (benzyl) -3,6,9, 15-tetraazabicyclo- [9.3. l]pentadeca-l (15) , 11, 13-triene 9.3 g (38.62 mmol) of the title compound from example 5c and 21.36 g (154.5 mmol) of potassium carbonate is dissolved in 200 ml of dimethylformamide and heated to 70°C. Within 30 minutes 26.43 g (154.5 mmol) of benzyl bromide is instilled and stirred for 24 hours at 70°C. , The solvent is removed in a vacuum and the residue is taken up in 250 ml of 3 N potassium hydroxide solution. It is extracted 5 times with 150 ml of methylene chloride and the organic phases are dried on magnesium sulfate. After concentration by evaporation in a vacuum it is chromato- - 67 - 91046/2 graphed on silica gel (mobile solvent: isopropanol/tri- ethylamine = 20/1) .

Yield: 17.97 g (91% of theory) of a slightly yellow oil .

Analysis: Calculated: C 75.20 H 6.90 N 10.97 CI 6.93 Found: C 75.11 H 6.98 N 10.85 CI 7.06 j b) 13-carboxy-3 , 6, 9-tris- (benzyl) -3,6,9, 15-tetraazabicyclo- [9.3. l]pentadeca-l (15) ,11, 13-triene A solution of 17.5 g (34.24 mmol) of the title compound from example 23a in 80 ml of 1, 2-dimethoxyethane is instilled into 1.95 g (79.44 mmol) of magnesium chips and heated to boiling. To this a solution of 6.43 g (34.24 mmol) of 1, 2-dibromoethane in 40 ml of 1, 2-dimethoxyethane is instilled over a period of 12 hours. j It is cooled in an ice bath and the solution is carefully poured on 10 g of Dry Ice. After 3 hours stirring at room temperature 200 ml of water is carefully added and ,it is brought to pH 4 with hydrochloric acid. It is evaporated to dryness and the residue is boiled out with 200 ml of ethanol. After filtering out the magnesium salts, it is again evaporated to dryness and the residue is again chroma-tographed on silica gel (mobile solvent: chloroform/-: methanol/triethylamine = 20/15/1) . ! Yield: 5.16 g (29% of theory) of a slightly yellow i solid.

Analysis: j Calculated: C 76.27 H 6.79 N 10.78 O 6.16 Found: C 76.19 H 6.88 N 10.71 1 - 68 - 91046/2 c) 13- (morpholinocarbonyl) -3 , 6, 9-tris- (benzyl) -3,6,9', 15-tetraazabicyclo [9.3.1 ] entadeca-1 (15) , 11, 13-triene 5.0 g (9.62 mmol) of the title compound from example 23b, 922 mg (10.58 mmol) of morpholine and 1.43 g (10.58 mmol) of 1-hydroxy-lH-benzotriazole hydrate are dissolved in 10 ml of absolute dimethylformamide and cooled to O^C: 2.18 g (10.58 mmol) of dicyclohexylcarbodiimide it is added and it is stirred for 1 hour at 0°C; then overnight at room temperature.

The solution is poured in 180 ml of ice water and extracted 3 times with 150 ml of chloroform. After drying of the organic phase on magnesium sulfate it is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: chloroform/methanol/tri-ethylamine = 20/5/1) . : 4.22 g (88% of theory) of the title compound is obtained as colorless oil.

Analysis : Calculated: C 75.48 H 7.19 N 11.90 O 5.44 : 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 from example 23c is dissolved in 250 ml of ethanol and 0.5 g of Pearlman catalyst (20% palladium hydroxide on carbon) is added.

After 24 hour hydrogenation in the autoclave (50°C arid 3 bars of hydrogen pressure) it is suctioned off from catalyst and concentrated by evaporation in a vacuum. The residue is recrystallized from 30 ml of tetrahydrofuran. ■ Yield: 1.85 g (83% of theory) of the title compound as white crystalline powder. 69 - 91046/2 Analysis: ; Calculated: C 60.16 H 7.89 N 21.93 O 10.02 | Found: C 60.08 H 7.97 N 21.81 e) 13- (morpholinocarbonyl) -3 , 6, 9-tris- (carboxymethyl) - 3,6,9, 15-tetraazabicyclo [9.3.1] entadeca-1 ( 15) , 11 , 13 -triene 1.5 g (5.0 mmol) of the title compound from example 23d is dissolved in 25 ml of water and 1.89 g (20 mmol) of chloroacetic acid is added. It is adjusted to pH 9.5 with 6 n potassium hydroxide solution. It is stirred for 12 hours at 45°C and the pH is maintained between 9.5 - 10 by addition of 6 N potassium hydroxide solution. j After working up an ion exchangers as described in example Id, after crystallization from methanol/acetone 1.66 g (67% of theory) of a strongly hygroscopic solid is obtained. ; Analysis: Calculated: C 53.54 H 6.33 N 14.19 O 25.94 ! Found: C 53.41 H 6.47 N 14.08 i f) Gadolinium complex of 13- (morpholinocarbonyl) -3 , 6 ,9-tris (carboxymethyl) -3,6,9, 15-tetraazabicyclo [ 9.3. l]penta-deca-l(15) , 11 , 13-triene i 1.5 g (3.04 mmol) of the title compound from example 23e is dissolved in 10 ml of deionized water and 551 mg (1.52 mmol) of gadolinium oxide is added. It is stirred for 3 hours at 90°C. The solution is filtered and the filtrate is freeze-dried .

Yield: 1.97 g (100% of theory) of a white amorphous powder which according to analysis contains 10.1% water. ί Analysis: ! Calculated: C 40.79 H 4.36 N 10.81 O 19.76 Gd 4.28 Found: C 40.71 H 4.44 N 10.89 Gd 24.17 Example for NMR diagnosis in vivo To a naked mouse Balb/c nu/nu, female, 20 g, with subcutaneous HT 29 colon carcinoma, after previous shots in the nuclear spin tomograph (producer: General Electric, 2 tesla) 0.1 mmol of gadolinium complex of 3,6,9-tris-(carboxy ethyl) -3 , 6 , 9 , 15-tetraazabicyclo [9.3.1]pentadeca-1 (15) , 11, 13-triene [example le] per kg is applied i.v. in a caudal vein. The substance was dissolved in bi-distilled water (pH 7.2). Shots were taken in spin-echo-sequence TR = 400 msec. , TE = 30 msec.

The shots were taken before and also 1, 23 and 43 minutes after application of the contrast medium in the area of the liver and of the tumor.

It was possible to show that the signal intensity in the tumor increased and did not fall again over the observed period.

The preceding examples can be repeated with siidilar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing fromm the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims (7)

- 73 - 91046/7 WHAT IS CLAIMED IS: Macrocyclic compounds of general formula wherein .... represents a single bond or double bond q is a number of 0 or 1; A and B, being the same or different, straight-chain or branched C2-6 alkylene group; r =CR3-; F is (-CHR8-)n or (=CR8-)n; Z is an H atom or the group -CH2C00Y with Y metal ion equivalents of at least one element with atomic numbers 21-29, 42, 44 or 57-83, or at least of one radionuclide of an element with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77; R1 is an H atom, a halogen atom, or a c1-c4 alkyl group ; R2 is H, C1-C4 alkyl, R3 is H, a halogen atom, a phenyl or a C^-C^ alkyl group, which alkyl group is optionally substituted by one or 5 6 7 more phenyl and/or hydroxy group (s); OR ; or -(C) ^N R or G; 0 - 74 - 91046/7 R is a hydroxy group, R or a C -C. alkyl group which is optionally hydroxylated or carboxylated; R5 is a C -C- alkyl radical optionally substituted by 1

1. 6 to 3 hydroxy groups; R6 and R7, independently from one another, are H, the radical R5, phenyl or benzyl radicals optionally substituted by 1 to 3 hydroxy groups, or R and R together with the nitrogen atom form a saturated or unsaturated 5 or 6 members ring optionally containing an additional N atom, 0 atom, s atom or a carbonyl group, said 5 or 6 member ring being optionally substituted by 1 to 3 radicals R5 , or one of the substituents R or R is -C-R ; R2 and R4 are each independently C5-C8 R° is R or G; m is 0 or 1; n is 0 or l; G is a second macrocycle of general formula II bonded by a direct bond, a bis (carbonylamino) group ( -NH-CO-CO-NH-) or by a C1~C2o alkylene group optionally having carbonyl (>CO) groups, carbonylamino (-NH-CO-) groups, or 0 atoms on the ends thereof and optionally contains one or more oxygen atom(s), Z-, Ci-io"acy1 groups, C1_1()-hydroxyacy 1 substituted imino groups, one to two C-C double bonds arid/or one to two C-C triple bonds ! - 75 91046/6 D has the meaning as D, with the exception that D does not contain the substituent G, or stands for the ,' radical -CH-, =C- or -N-; and has the same meaning as F, with the exception that F1 does not contain the substituent G, or stands for the radical -C IH- or =C I-; as well as the salts thereof formed with inorganic and/or organic bases, amino acids or amino acid amides!; with the proviso that at least two substituents z stand for the radical -CH2C00Y and the macrocyclic compound of general formula I contains not more than one radical G, if n stands for the number 0 and the 5 member ring thus formed is to be unsaturated, then the double bonds are located between positions 2,3 and 4,5 of the 5 member ring, and said compound is neither 3 , 6 , 9-tris- (carboxymethyl ) -3 , 6 , 9 , 15-tetraazabicyclo (9 , 3 , 1) pentadeca-1 ( 15) , 11 , 13-triene nor the Cu, Pb, Co and Sr complexes thereof.

2. A compound according to claim 1, wherein G is a ring of general formula II bonded by i - 76 - 91046/6 -(CH2) 1_6-, -0-(CH2)1_6-0-, -C-(CH2 ) 1_6-i'- , -C^C-CBC, or o o ! M II -NH-C-(CH_)_ ,-C-NH- group.

3. Λ pharmaceutical media comprising at least one physJologlcnlly acceptable compound of general formula I wherein .... represents a single bond or double bond; q is a number of 0 or 1 ; Λ and B, being the same or different, are each straight-chain or branched C_ , alkylene group; 2 3 3 D is N, 0, =C=0, =HR , -CHR -, or =CR - E is N, S, 0, - - = or NR4; F is (-CHR8-)N or (=CR8-)N; Z is an H atom or the group -CH2C00Y with Y metal ion equivalents of at least one element with atomic numbers 21-29, 42, 44 or 57-83, or at least of one radionuclide of nn element with atomic numbers 27, 29, 31, 32, 37-39, 3 49, 62, 64, 70 or 77; U1 is an H atom, a halogen atom, or a C^-C^ alkyl group; n2 is II, C -C alkyl, - 76A - 91046/5 R is H, a halogen atom, a phenyl or a ci~c^ alkyl group, which alkyl group is optionally substituted by one or -9 . 7 . more phenyl and/or hydroxy group(s); OR5; or -(C) NR6R7i or c- I I m ; o 4 . 2 : ~ R is a hydroxy group, R or a C -C alkyl group which is optionally hydroxylated or carboxylated ; R5 is a C -C, alkyl radical optionally substituted by 1 X 6 ; to 3 hydroxy groups; R6 and R7, independently from one another, are H, the radical R5, phenyl or benzyl radicals optionally substituted 9.7.09 6 7 by 1 to 3 hydroxy groups, or R and R together with the nitrogen atom form a saturated or unsaturated 5 or 6 members ring optionally containing an additional N atom, 0 atom, s atom or a carbonyl group, said 5 or 6 member ring being 5 optionally substituted by 1 to 3 radicals R , or one of the substituents R or R is ; 1 2 . 4 R , R and R are each independently Cc--C R8 is R1 or G; y . 7 . 89 m is 0 or 1 ; n is 0 or 1; G is a second acrocycle of general formula II bonded by a direct bond, a bis (carbonylamino) group (-NH-CO-CO-NH-) or by a c1~<-20 al^yiene group optionally having carbonyl (>CO) groups, carbonylamino (-NH-C0-) groups, or 0 atoms on the ends thereof and optionally contains one or more oxygen atom(s), Z-, C1_10-acyl groups, Οχ_ 1Q-hydroxyacy 1 substituted i ino groups, one to two C-C double bonds a!nd/or one to two C-C triple bonds (II), - 76B - 91046/5 13 has the meaning as D, with the exception that D does not contain the substituent G, or stands for the I I i radical -CH-, =C- or -N-; and i has the same meaning as F, with the exception that F1 does not contain the substituent G, or stands for the radical -C IH-, as well as the salts thereof formed with inorganic and/or organic bases, amino acids or amino acid amides; with the proviso that at least two substituents z stand for the radical -CH2COOY and the macrocyclic compound of general formula I contains not more than one radical G, optionally with the additives usual in galenicals.

4. Λ pharmaceutical media comprising at least one physiologically acceptable compound according to claim 2, optionally with the additives usual in galenicals.

5. In a method for the production of media for use in NMR diagnosis, X-ray diagnosis, radiodiagnosis , radiotherapy or radiation therapy, the improvement wherein said media contains at least one physiologically acceptable compound according to claim 3. !

6. Λ process for the production of macrocyclic compounds of Formula I ( I ) . - 77 91046/7 whore.in .·_·_·-.·. represents a single bond or double bond q is a number of 0 or 1/ Λ and D, being the same or different , straight-chain or branched c2-6 al -ylene group; D is N, 0, =C=0, =N 2, -CHR3-, or =CR3-; is M , S, 0, -Νί+)-, =C- or NR ; (-) OH F is (-CIIR -)n or (=CR -) ; Z is an H atom or the group -CII2C00Y with Y metal ion equivalents of at least one element with atomic numbers 2.1.-29, 42, 44 or 57-83, or at least of one radionuclide of an element with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70 or 77; R is an H atom, a halogen atom, or a C.-C. alkyl to 3 hydroxy groups; j 6 7 1 R and R , independently from one another, are H, the radical R5 , phenyl or benzyl radicals optionally substituted 6 7 by 1 to 3 hydroxy groups, or R and R together with the nitrogen atom form a saturated or unsaturated 5 or 6-membered ring optionally containing an additional N atom, 0 atom, s atom or a carbonyl group, said 5 or 6-membered ring being 5 ; optionally substituted by 1 to 3 radicals R , or one of, the substituents R or R' and R are each independently C - 78 - 91046/3 R° is R or G; m is 0 or 1; n is 0 or 1; G is a second macrocycle of general formula II bonded by a direct bond, a bis (carbonylamino) group (-NH-CO-CO-NH-) or by a c^~C2o alkylene group optionally having carbonyl (>CO) groups, carbonylamino (-NH-CO-) groups, or 0 atoms on the ends thereof and optionally contains one or more oxygen atom(s) , Z-, groups, C1_10-hydroxyacyl substituted imino groups, one to two C-C double bonds and/ or one to two C-C triple bonds D1 has the meaning as D, with the exception that D1 does not contain the substituent G, or stands for the radical -CH-, =C- or -N-; and ! F1 has the same meaning as F, with the exception that F1 does not contain the substituent. G, or stands for |the j radical -CH- or =C-; j as well as the salts thereof formed with inorganic and/or organic bases, amino acids or amino acid amides; with the proviso that at least stand for the radical -CH2COOY and the of general formula I contains not more comprising alkylating compounds in which J- j. ι X stands for ΐ. or for a 5 or 6-member d ring j to be converted into the desired ring; j with a halogen compound of formula III i HalCH2COOY' (HI), ί in which Hal stands for chlorine, bromine or iodine and Y' stands for a hydrogen atom or an acid protecting ί group, I and then, optionally after conversion of X into the desired 5- or 6-membered ring of the end product andj optionally after cleavage of the protecting group Y · > op- ' tionally the complexing agents of formula I with Y meaning hydrogen thus obtained are reacted with at least one; metal oxide or metal salt of an element with atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83 and then, if desired, acid hydrogen atoms still present are substituted by cations of inorganic and/or organic bases, amino acids or animo| amides; with the proviso that at least two substituents z stand for the radical -CH COOY and the macrocyclic compound 80 - 91046/3 of general formula I contains not more than one radical G, if n stands for the number 0 and the 5-member ring thus formed is to be unsaturated, then the double bonds are located between positions 2,3 and 4,5 of the 5-member ring, and said compound is neither 3 , 6 , 9-tris- (carboxymethyl);-3 , 6 , 9 , 15-tetraazabicyclo (9 ,3 ,1) pentadeca-1 (15 ) ,11 ,13-triene nor the Cu, Pb, Co and Sr complexes thereof.

7. In a process for the production of pharmaceutical media containing conventionally used additives in galenicals and wherein the media is produced in a form suitable for eriteral or parenteral application, the improvement comprising: said pharmaceutical media being a media according to claim 5 and wherein the complex compound is dissolved or suspended in water or physiological saline solution. for the Applicant: i WOLFF, BREGMAN AND GOLLER I