IL103996A - Process for the production of mono-n-substituted tetraazacyclododecane and tetraazacyclo- tetradecane derivatives - Google Patents

Abstract

A novel process for the preparation of mono-N-substituted tetraazamacrocycles is described.

Description

103,996/2 Ί πι^ ^ΝΐΝΝΊυυ ηπ^ιη ρ?ηη Τ\ΓΗ Ν-1 θ αΠΙΟΠ ρ7ΝΊϋϋ^ρ^ΝΤΣΧΝΊ \?1 PROCESS FOR THE PRODUCTION OF MONO-N-SUBSTITUTED TETRAAZACYCLODODECANE AND TETRAAZACYCLOTETRADECANE DERIVATIVES 1 103,996/2 The present invention relates to a process for the production of mono-N-substituted tetraazacyclododecane and tetraazacyclotetradecane derivatives.

Background of the Invention Mono-N-substituted tetraaza macrocycles of general formula I: in which: n stands for the numbers 2 or 3; R stands for a β-carboxy alkyl or β-alkoxycarbonyl alkyl, β-cyanide alkyl, β-carboxamido alkyl, β-hydroxy alkyl, aminocarbonyi, aminothiocarbonyl, β-sulfamoylalkyl radical or for a second tetraazacyclododecane or tetraazacyclotetradecane molecule bound by a bis^-hydroxy)-alkylene chain, and carboxyl and hydroxy groups are present optionally in protected form, are important precursors of tri-N-carboxyalkyl, preferably tri-N-carboxymethyl, substituted tetraaza macrocycles, - 2 - 103,996/2 which are used as diagnostic agents and therapeutic agents in the form of their complexes with metal ions of atomic numbers 21 to 29, 31, 32, 38, 39, 42-44, 49 or 57-83 (see European patent application publication no. 255471) .

Because of their importance as key compounds for these complexes, above all for the preferred NMR diagnostic agents (Macrocyclic Chemistry Congress, Hamburg 1988) , production of mono-N-substituted tetraaza macrocycles has been attempted in different ways, but without a satisfactory method of synthesis previously having been found.

For example, a statistical monoalkylation or monoacylation of unsubstituted tetraaza macrocycles has been described, which, however, is not suitable at least for the production of sizable amounts of substance because of the great excess of relatively costly initial amine to be used, partially very expensive chromatographic separation of the product from the initial material as well as in most cases quite moderate yields, [see Kaden, Helv. Chim. (Swiss Chem.) Acta 69, 2081 (1986); Kimura, J. Chem.

Soc. Chem. Commun. 1158 (1986) ; Kaden, Top. Curr. Chem. 121, 157 (1984); European Patent Application No. 296522, corresponding to IL 86835; and European Application 353450.] If it is desired - in contrast to the above-described statistical monosubstitution — to perform a specific monosubstitution, two variants are possible: a) reaction of a tetraaza macrocycle, provided with three nitrogen protecting groups, which was obtained by statistical trisubstitution, b) reaction of a tetraaza macrocycle, provided with three nitrogen protecting groups, which was produced by specific synthesis.

In the first-mentioned variant, the precursor carrying the protecting groups (e.g., tosylate, benzoate) on three nitrogen atoms is produced by statistical trisubstitution of an unsubstituted tetraaza macrocycle, so that the above- mentioned drawbacks of a statistical reaction, such as low yields, separating problems (particularly, in the production of sizable amounts of substance) also occur here [see, e.g., Macrocyclic Chemistry Congress, Hamburg 1988]. After the subsequent specific monosubstitution to introduce substituent R [Ciampolini, J. Chem. Soc. Chem. Commun. 998 (1984): Kaden, Helv. Chim. Acta 66, 861 (1983); Basefield, Inorg. Chem. 25, 4663 (1986)], the protecting groups on the three nitrogen atoms have to be removed, e.g., by alkali metal in ammonia [Helv. Chim. Acta, 56, 2216 (1973) ; Helv.

Chim. Acta 59, 1566 (1976); J. Org. Chem. 53, 3521 (1988)], lithium aluminum hydride [F. Voegtle; Liebigs Ann. Chem. (1977) , 1344], Red-Al(R) [E. H. Gold, J. Org. Chem. (1972), 37, 2208], Na-Hg [M. Kellog, J. Org. Chem. 1984, 49, 110], electrolysis [M. Hesse, Helv. Chim. Acta 71 (1988), 7, 1708] or hydrobromic acid/phenol/glacial acetic acid [N. G. Lukyanenko, Synthesis, 1988, 355]. These processes of the cleavage of the protecting groups are generally connected with poor yields, limit the batch size with respect to the amount of reagent to be used (e.g. , in the Na-Hg method) and above all cannot be used in the case of substituents, which carry sensitive groups (e.g., hydroxyalkyl) .

If the procedure is performed according to variant b) , i.e., if it is desired to produce the tetraaza macrocycle precursor carrying protecting groups on three nitrogen atoms by specific synthesis, a start is made from two reactants, which are cyclized according to methods known in the literature [e.g., Rich an, Org. Synthesis 5_8, 86 (1978) ; Atkins, J. Amer. Chem. Soc. 96, 2268 (1974)]; one of the two reactants contains a protected nitrogen atom and carries, on the chain end, two volatile groups (e.g., bromine, mesyloxy, tosyloxy, triflate or alkoxycarbonyl groups) , which are nucleophilically displaced from the terminal nitrogen atoms of the second reactant, of a — unlike the first reactant — protected triaza compound.

(If a reactant with two terminal ester groups is used, the two amide groupings resulting by the cyclization — preferably with diborane in THF — have to be reduced. But especially this cyclization variant is unsuitable for the production of substantial amounts of substance, since this reaction is to be performed in the highest possible dilution, to avoid, e.g., polymerization reactions: see Tabushi, Tetrahed. Lett. 12, 1049 (1977); Kaden, Inorg. Chem. 25, 321 (1986) . Also, the working up of the subsequent diborane reduction — again above all in greater batches — is not without problems . ) After cleavage of one protecting group, the thus released imino grouping can be alkylated or acylated. As an example, there can be mentioned the reaction of the disodium salt of Ν,Ν' ,N"-tris- (p-tolylsulfonyl) diethylene triamine [Ciampolini, J. Chem. Soc. Chem. Commun. 998 (1984)] with N-bis- (2-methanesulfonyloxy-ethyl) -triphenylmethylamine in dimethylformamide at 80-150°C with subsequent cleavage of the trityl group under acid conditions. The yields of both reaction steps are generally poor. Also, this variant b) is affected with the drawbacks mentioned under a) regarding the cleavage of three protecting groups coming from the second reactant.

Besides the previously presented process of the statistical and specific monosubstitution, a specific ring synthesis, in which desired substituent R already is contained in one of the two reactants to be used in the cyclization reaction, is also possible.

Besides the problems, already described above, of the cleavage of the protecting groups, it has turned out that the thus performed cyclizations generally take place with smaller yields — as compared to the reactions of the reactant provided only with protecting groups — [see Atkins, J. Amer. Chem. Soc. 96, 2268 (1974); Richman, Org. Synthe-sis 58/ 86 (1978); Fabbrizzi, Inorg. Chem. 25, 4131 (1986); 5 103,996/2 Gazetta, Chimica Italiana 1 15, 399 (1985)]. Further, the reactants carrying substituent R first have to be specially synthesized in a reaction sequence often comprising several steps [see, e.g., Bulkowski, J. Org. Chem. 47, 412 (1982)].

Despite varied efforts, it therefore previously has not been possible to find a satisfactory method of synthesis for mono-N-substituted tetraaza macrocycles of general formula I, which are to be considered as key compounds for the tri-N-carboxyalkyl metal complexes being used as valuable NMR and x-ray contrast media.

Summary of the Invention An object of the invention, therefore, is to make available a process for production of mono-N-substituted tetraaza macrocycles, which is suitable above all for the production of substantial amounts of substance.

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 achieved by the present invention.

Thus, the invention provides a process for the production of mono-N-substituted tetraazacyclododecane and tetraazacyclotetradecane derivatives of general formula I: in which: n stands for the numbers 2 or 3; 103,996/ 3 R stands for a β-carboxy alkyl or β-alkoxycarbonyl alkyl, β-cyanide alkyl, β-carboxamido alkyl, β-hydroxy alkyl, aminocarbonyl, aminothiocarbonyl, β-sulfamoylalkyl radical or for a second tetraazacyclododecane or tetraazacyclotetradecane molecule bound by a bis^-hydroxy)-alkylene chain, wherein "alkyl" in β-carboxy alkyl, β-alkoxycarbonyl alkyl, β-cyanide alkyl, and β-carboxamido alkyl stands for -CR^-CHR1-; "amido" in β-carboxamido alkyl stands for CONR5R6; "alkyl" in β-hydroxy alkyl stands for -CHR7CHR8-; "amino" in aminocarbonyl and aminothiocarbonyl stands for X 6A 103,996/ 1 (with. X in the meaning of an oxygen or sulfur atom), "sulfamoyl" in P-sul&moylalkyl stands for -NHS02Rl°; and "alkylene" in bis(p- hydroxy)-alkylene stands for K R1 stands for a hydrogen atom, a straight-chain or cyclic Ci-Ce alkyl, a phenyl or benzyl group in which the phenyl or benzyl group can be substituted respectively by 1 to 2 chlorine, bromine, nitro, C 1-C7 alkoxy, C7-Ci0 aralkoxy and/or C02R4 radicals, with R4 meaning a hydrogen atom, a Ci.C6 alkyl, phenyl or benzyl group; R2 and R3, independent of one another, each stand for R1 or a CO2R4 group; R5 and R6, independent of one another, each stand for a hydrogen atom, a saturated or unsaturated, straight-chain, branched-chain or cyclic hydrocarbon radical with up to 16 carbon atoms optionally interrupted by 1 to 8 oxygen atoms or 1 to 3 phenylene or phenylenoxy groups, and optionally substituted by 1 to 5 hydroxy groups or 1 to 2 C02R4 radicals; for phenyl or benzyl radicals optionally substituted by 1 to 3 hydroxy or Cp alkoxy groups; or R5 and R6 together with the nitrogen atom stand for a saturated or unsaturated, 5- or 6-ring oxygen, sulfur atom or carbonyl group optionally containing another nitrogen, which optionally is substituted by 1 to 3 CrC6 alkyl radicals optionally substituted by 1 to 3 hydroxy radicals, and optionally present hydroxy and/or carboxyl groups optionally are protected; R and R , independent of one another, respectively stand for a hydrogen atom, a C1-C20 alkyl radical, optionally interrupted by 1 to 10 oxygen atoms, a phenylene, phenylenoxy or phenylenedioxy group, which optionally is substituted by 1 to 3 CrC6 alkyl, 1 to 3 trifluoromethyl, 1 to 7 hydroxy, 1 to 3 CrC7 alkoxy, 1 to 3 CrC10 aralkoxy, 1 to 2 C02R4 and/or 1 to 2 phenoxy or phenyl groups optionally substituted by 1 to 2 chlorine, 6B 103,996/ l bromine, m'tro or Ci-C^ alkoxy radicals, and the optionally present hydroxy radicals optionally are present in protected form; R9 stands for a phenyl, 1 or 2 naphthyl or straight-chain or cyclic Ci-C6 alkyl group; R10 stands for a CrC6 alkyl, -CF3 or a phenyl group optionally substituted by a C\-C6 alkyl, chlorine, bromine, or nitro radical; K stands for a C0-CI6 alkylene chain optionally substituted by 1 to 6 hydroxy, 1 to 6 C1-C7 hydroxyalkyl, 1 to 8 CrC7 alkoxy, 1 to 8 C7-Ci0 aralkoxy and/or 1 to 2 benzyloxy groups, and optionally interrupted by 1 to 6 oxygen atoms, 1 to 2 phenylene, phenylenoxy or phenylenedioxy groups; and wherein carboxyl and hydroxy groups are present optionally in protected form; characterized in that the compounds of general formula Π obtained from 1,4,7, 10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane are reacted with an α,β-unsaturated ester, amide or nitrile, or an epoxide, isocyanate, isothiocyanate, aziridine or a bisepoxide, with or without solvent, at 0-220°C, preferably room temperature to 210°C, within 1 to 48 hours, preferably 5 to 12 hours, optionally at a pressure up to 100 atm; then the thus-obtained reaction mixture, after cooling to -20-80°C, preferably 0-30°C, is mixed with a mixture of water/organic solvent and stirred 6C 103,996/1 for 0.5-12 hours, preferably 0.5-3 hours at -20°C to room temperature, preferably 0°C to room temperature; then the thus-formed, optionally to be isolated, intermediate products carrying a formyl group on a nitrogen atom are reacted by adding an inorganic base or an acid at 0-150°C, preferably room temperature to 120°C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring, optionally followed by subsequent removal of protecting groups in a way usual in the art, to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride.

The tetraazatricyclotridecane or tetraazatricyclopenta-decane of general formula II used as intermediates are accessible according to methods known in the literature, e.g., by reacting 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane with dimethylformamide-dimethylacetal (US patents 4,085,106 and 4,130,715), J. Am. Chem. SOC. 102, 6364 (1980), EP 292 689.

Advantageously, this reaction step is included in the process according to the invention, without the intermediates of general formula II having to be isolated ("one-pot reaction") .

A special embodiment of the process according to the invention is the production of compounds of general formula I with R2 R1 I I R meaning a —C—CH-A group, in which R1 stands for a hydrogen atom, a straight-chain or cyclic Ct-C6 alkyl, a phenyl or benzyl group — in which the phenyl or benzyl group can be substituted respectively by 1 to 2 chlorine, bromine, nitro, C^-C7 alkoxy, C7-C10 4 . 4 . aralkoxy, and/or C02R radicals with„R meaning a hydrogen atom, a C -C6 alkyl, phenyl or benzyl group, 2 3 · R and R , independent of one another, each stand for 1 4 R or a C02R group, R5 4 / A stands for a CN, C02R or CON radical, V in which R5 and R6, independent of one another, each stand for a hydrogen atom, a saturated or unsaturated, straight-chain, branched-chain or cyclic hydrocarbon radical with up to 16 C atoms, optionally interrupted by 1 to 8 oxygen atoms, or 1 to 3 phenylene or phenylenoxy groups, and optionally substituted by 1 to 5 hydroxy groups, or 1 to 2 C02R radicals; for phenyl or benzyl radicals optionally - 8 - substituted by 1 to 3 hydroxy or C^-C6 alkoxy groups; or R and R6 together with the nitrogen atom stand for a saturated or unsaturated 5- or 6-ring, optionally containing another nitrogen, oxygen, sulfur atom or a carbonyl group, which optionally is substituted by 1 to 3 C-C6 alkyl radicals optionally substituted by 1 to 3 hydroxy groups, and optionally present hydroxy and/or carboxyl groups optionally are protected, characterized in that tetraazatricyclotridecane or tetraazatricyclopentadecane is reacted with a feedstock of general formula III in which R1, R2, R3 and A have the above-indicated meanings, and optionally present hydroxy and/or carboxyl groups are optionally protected, with or without solvent, preferably aprotic solvents, such as, e.g. , benzene, toluene, dich1oromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or ether, are used as solvent, at 0°C to 210°C, preferably 50°C to 180°C (and in the case of the higher reaction temperature, the solvent used optionally to dissolve the added feedstock of general formula III was previously distilled off in a vacuum) , within 12 to 48, preferably 5 to 12 hours. The thus obtained reaction mixture is cooled to -20°C to 80°C, preferably 0° to 30°C, mixed with a mixture of water/organic solvent, such as, e.g., methanol, ethanol, isopropanol, tetrahydrofuran or dioxane, and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours, at -20°C to room temperature, preferably 0°C to room temperature. The thus formed — optionally to be isolated — intermediate product carrying a formyl group on a nitrogen atom is reacted by adding an inorganic base such - 9 - as, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid, such as, e.g., hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at 0°C to 150°C, preferably room temperature to 120°C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring optionally followed by subsequent removal of protecting groups in a way usual in the art — to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride.

If R1 stands for a ^-C6 alkyl group, the methyl and ethyl group is preferred. Other preferred radicals for R are the hydrogen atom and the optionally substituted phenyl radical. As preferred substituents on the phenyl ring, the nitro group, the ^-C7 alkoxy radical, above all the methoxy and ethoxy radical, and the C02R radical, can be mentioned, with R4 being preferably hydrogen, methyl, ethyl, t-butyl or benzyl.

As preferred radicals standing for R5 and R6, hydrogen, methyl, ethyl, 2-hydroxyethyl, 2-hydroxy-l- (hydroxymethyl) -ethyl, 1- (hydroxymethyl) -ethyl, propyl, isopropenyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, butyl, isobutyl, isobutenyl, 2 -hydroxybuty1 , 3-hydroxybutyl, 4-hydroxybuty1, 2-, 3- and 4-hydroxy-2-methylbutyl, 2- and 3-hydroxyisobutyl, 2,3,4-trihydroxybutyl , 1, 2 , -trihydroxybutyl , pentyl, cyclopentyl, 2-methoxyethyl, hexyl, decyl, tetradecyl, triethylene glycol methyl ether, tetraethylene glycol methyl ether and methoxybenzyl group can be mentioned. The amide radical can also be a heterocyclic 5- or 6-ring formed with the inclusion of the amide nitrogen. As examples, there can be mentioned: pyrrolidinyl, piperidyl, pyrazolidinyl, pyrrolinyl, pyrazolinyl, piperazinyl, morpholinyl, imidazolidinyl , oxazolidinyl , and thiazolidiny1. - 10 - In substrate III, optionally present carboxyl and/or hydroxy groups are present preferably in protected form.

As acid protecting groups, lower alkyl (e.g., C ) , aryl (e.g., C6.10) and aralkyl (e.g., C7.12) groups, for example, the methyl, ethyl, propyl, n-butyl, t-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis (p-nitrophenyl) -methyl group as well as trialkylsilyl (e.g., with C^-alkyl groups) groups, are suitable.

The cleavage of the protecting groups 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 of 0 to 50°C, acid saponification with mineral acids or in the case of, e.g., tert-butyl esters with the help of trifluoroacetic acid.

As hydroxy protecting groups, e.g., benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl, and diphenyl-t-butylsilyl groups are suitable.

The hydroxy groups can also be present, e.g., as THP-ether, a-alkoxyethylether (e.g., with C -alkoxy groups) , MEM-ether or as esters with aromatic or aliphatic carboxylic acids, such as, e.g., acetic acid or benzoic acid. In the case of polyols, the hydroxy groups can also be protected in the form of ketals with, e.g., acetone, acetaldehyde, cyclohexanone or benzaldehyde.

The hydroxy protecting groups can be released according to the methods in the literature known to one skilled in the art, e.g. , by hydrogenolysis, reductive cleavage with lithium/ammonia, acid treatment of the ethers and ketals or alkali treatment of the esters (see, e.g., "Protective Groups in Organic Synthesis," T. W. Greene, John Wiley and Sons 1981) .

Another special embodiment of the process according to the invention is the production of compounds of general formula I with R meaning a - 11 - OH -CH-C IH-R. group, in which 7 8 R and R , independent of one another, respectively stand for a hydrogen atom, a C^-C2Q alkyl radical, optionally interrupted by 1 to 10 oxygen atoms, a phenylene, phenylenoxy or phenylenedioxy group, which optionally is substituted by 1 to 3 ^-C6 alkyl, 1 to 3 trifluoromethyl, 1 to 7 hydroxy, 1 to 3 C-C7 alkoxy, 1 to 3 C7-C10 aralkoxy, 1 to 2 C02R and/or 1 to 2 phenoxy or phenyl groups optionally substituted by 1 to 2 chlorine, bromine, nitro or C^-C6 alkoxy radicals, and the optionally present hydroxy radicals are optionally in protected form, characterized in that tetraa z atr icyc lotr idecane or tetraazatricyclopentadecane is reacted with a feedstock of general formula IV R7 R8 7 8 in which R and R have the above-indicated meaning and wherein optionally present hydroxy and/or carboxyl groups optionally are protected, with or without solvent, preferably aprotic solvents, such as, e.g., benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexane or ether are used as solvent, at 0°C to 220°C, preferably 50°C to 180°C (and in the case of the higher reaction temperature, the solvent optionally used to dissolve the added feedstock of general formula IV was previously distilled off in a vacuum) or in an autoclave at an excess pressure of 1 to 100 atm. within 1 to 48 hours, preferably 5 to 12 hours. The thus obtained reaction mixture is cooled to -20°C to 80°C, preferably 0°C to 30°C, mixed with a mixture of water/organic solvent, such as, e-g-, methanol, ethanol, isopropanol, tetrahydrofuran or dioxane and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours, at -20 °C to room temperature, preferably 0°C to room temperature. The thus formed — optionally to be isolated — intermediate product carrying a formyl group on a nitrogen atom is reacted by adding an inorganic base, such as, e.g. , lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid, such as, e.g., hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at 0°C to 150 °C, preferably room temperature to 120 °C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring — optionally followed by subsequent removal of the protecting groups in a way usual in the art — to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride . 7 8 Preferred radicals R and R are hydrogen, methyl, ethyl, hydroxymethyl , 2-hydroxyethyl , 2 -hydroxy- 1- (hydroxymethyl) -ethyl , 1- (hydroxymethyl) -ethyl , propyl , isopropenyl, 2 -hydroxypropy1 , 3 -hydroxypropyl , 2 , 3-dihydroxypropyl , butyl, isobutyl, isobutenyl, 2-hydroxybuty1 , 3-hydroxybuty1 , 4-hydroxybuty1 , 2-, 3- and 4-hydroxy-2-methylbutyl , 2- and 3-hydrox isobuty1 , 2,3,4-trihydroxybutyl , 1 , 2 , -trihydroxybutyl , pentyl , cyclopentyl, 2-methoxyethyl, hexyl, decyl, tetradecyl, triethylene glycol methyl ether, tetraethylene glycol methyl ether and methoxybenzyl as well as -α^-Ο-Ο,,Η^-ΟΗ, -CH2-0-C6H4-0- (CH2CH20) 2-CH3, -CH2-0-C6H4-0- (CH2CH20) ^C^H^ , -CH2-0-C6H4-O-C4H8-OH, -(CH2CH20)5-CH3, - 13 - -(¼Η18-ΟΗ, -C^g-COOH, -CH2-0-C6H4-0-C6H12-COOH, -CH2-O-C6H-O-C4H8-0-CH2-CH0H-CH2OH, -CH2-O-C10H20-COOH, -CH2-0-C6H4-Cl, -CH2-0-C6H4-N02, -CH2-0-C6H3Cl2, -CH2-0-C6H4-COOH, -CH2-0-CH2-CHOH-CH2OH, -CHOH-CH2OH, -CH2-0-C6H4-0-CH2-COOH and —CH2—O—C6H4—CjH^ .

In the use of volatile epoxides, such as, e.g., ethylene oxide or propylene oxide, the reaction is performed in an autoclave.

In substrate IV, optionally present carboxyl and/or hydroxy groups are present preferably in protected form, as described above in the case of substrate III.

Another special embodiment of the process according to the invention is the production of compounds of general formula I with R meaning a -C-NHR radical, II X in which X means an oxygen or sulfur atom and R9 means a phenyl, 1- or 2-naphthyl or straight-chain or cyclic C,-C6 alkyl group, characterized in that tetraazatricyclotridecane or tetraazatricyclopentadecane is reacted with a feedstock of general formula V R9-N=C=X (V) , in which X and R have the above-indicated meaning, - 14 - with or without solvent, preferably aprotic solvents, such as, β·9·, benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or ether, are used as solvent, at 0°C to 180 °C, preferably room temperature to 150°C (and in the case of the higher reaction temperature, the solvent used optionally to dissolve the added feedstock of general formula V was distilled off previously in a vacuum) , within 1 to 48 hours, preferably 5 to 12 hours. The thus obtained reaction mixture is cooled to -20°C to 80°C, preferably 0°C to 30°C, mixed with a mixture of water/organic solvent, such as, e.g., methanol, ethanol, isopropanol, tetrahydrofuran or dioxane, and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours, at -20°C to room temperature, preferably 0°c to room temperature. The thus formed — optionally to be isolated —intermediate product carrying a formyl group on a nitrogen atom is reacted by adding an inorganic base such as, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid, such as, e.g., hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at 0°C to 150°C, preferably room temperature to 120°C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride.

Still another special embodiment of the process according to the invention is the production of compounds of general formula I with R meaning a - (CH2)2-NH-S02-R10 radical, in which R10 means a C^~C6 alkyl, -CF3 or a phenyl group optionally substituted by a C,-C6 alkyl, chlorine, bromine or nitro radical, - 15 - characterized in that tetraazatricyclotridecane or tetraazatricyclopentadecane is reacted with a feedstock of general formula VI in which R10 has the above-indicated meaning, with solvent, preferably aprotic solvents, such as, e.g. , benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or ether, are used as solvent, at 0°C to 180°C, preferably room temperature to 150 °C (and in the case of the higher reaction temperature, the solvent used was distilled off previously in a vacuum) , within 1 to 48 hours, preferably 5 to 12 hours. The thus obtained reaction mixture is cooled to -20°C to 80°C, preferably 0°C to 30°C, mixed with a mixture of water/organic solvent, such as, e.g. , methanol, ethanol, isopropanol, tetrahydrofuran or dioxane, and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours, at -20 °C to room temperature, preferably 0"C to room temperature. The thus formed — optionally to be isolated — intermediate product carrying a formyl group on a nitrogen atom is reacted by adding an inorganic base such as, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid, such as, e.g., hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at 0°C to 150°C, preferably room temperature to 120°C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring to the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride.

Preferred radicals R0 are the phenyl radical and 4-methylphenyl radical. - 16 - Another special embodiment of the process according to the invention is the production of dimers, i.e., compounds of general formula I with R meaning a second 1,4,7,10-tetraazacyclododecane or 1, 4 , 7 , 10-tetraazacyclotetradecane molecule bound by a bis(B-hydroxy)-alkylene chain -CH,-CH-K-CH-CH,- I I OH OH in which K means a C0-C16 alkylene chain optionally substituted by 1 to 6 hydroxy, 1 to 6 C-C7 hydroxyalkyl, 1 to 8 C^-C7 alkoxy, 1 to 8 C7-C10 aralkoxy, and/or 1 to 2 benzyloxy groups, and optionally interrupted by 1 to 6 oxygen atoms, 1 to 2 phenylene, phenylenoxy or phenylenedioxy groups, and the optionally present hydroxy groups optionally are present in protected form, characterized in that tetraazatricyclotridecane or tetraazatricyclopentadecane is reacted with a feedstock of general formula VII CH,-CH-K-CH-CH, (VII) , \2/ \ / O o in which K has the above-indicated meaning, and optionally present hydroxy groups are optionally protected, with or without solvent, preferably aprotic solvents, such as, e.g., benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or ether, are used as solvent, at 0°C to 220°C, preferably 50°C to 180°C (and in the case of the higher reaction temperature, the solvent used optionally to dissolve the added feedstock of general formula VII was distilled off previously in a vacuum) or in an autoclave at an excess pressure of 1 to 100 atm. within 1 to 48, preferably 5 to 12 hours. The thus obtained reaction mixture is cooled to -20°C to 80°C, preferably 0° to 30°C, mixed with a mixture of water/organic solvent, such as, e.g., methanol, ethanol, isopropanol, tetrahydrofuran or dioxane, and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours, at -20°C to - 17 - room temperature, preferably 0°C to room temperature. The thus formed — optionally to be isolated — intermediate product carrying a formyl group on a nitrogen atom is reacted by adding an inorganic base such as, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid, such as, e.g. , hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at 0°C to 150°C, preferably room temperature to 120 "C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring — optionally followed by subsequent removal of protecting groups in a way usual in the art — to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride.

Preferred binding links K are, for example, -C2H4- -CH2- -CH2-0-CH2- -CH2-0-CH2-CH2-0-CH2- -CH2-0- (CH2CH20) 2-CH2- -CHOH- -CHOH-CHOH- -CHOH-CHOH-CHOH- -CH2-0-CH2-CHOH-CH2-0-CH2- -CH2-0-C6H4-0-CH2- -CH2-0-C4H8-0-CH2- -C(CH2OH)2- -CH(CH2OH)- -CH2-0-C6H4-0-C6¾-0-CH2- -CHOH-CHOH-CHOH-CHOH- -CH2-0-CH2-CH (CH2OH) 2-CH2-0-CH2- -CH2-CH (CH2OCH3) -CH2- -CH(0CH3) - -CH2-0-CH2-C6H4-CH2-0-CH2- - 18 - In contrast to substrates III to VI, which — as compared with feedstock II — are reacted equimolarly to any excess, preferably with 1.05 to 2.0 equivalents, substrate VII is used in a deficiency of 0.5 to 0.3 equivalents.

In substrate VII, optionally present hydroxy groups are present preferably in protected form, as described above in the case of substrate III.

The above-described process according to the invention is distinguished by high yields, a small number of reaction steps, great variation range in desired substituents R, problem-free performance of large batches (upscaling) , partially by possible dispensing with solvent, as well as problem-free purification of the end products.

The following examples are used to explain the object of the invention in more detail.

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. - 19 - E X A M P L E S Reactions with compounds of general formula Example 1 a) Mixture of 1- and 4-formamido-10- [ (2-ethoxycarbonyl) -ethyl] -1 , 4,7 , 10-tetraazacyclododecane 15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1 , 4 , 7 , 10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is partially distilled off in this way. Then, 13.94 g (139.2 mmol) of acrylic acid ethyl ester is instilled under a nitrogen atmosphere and heated slowly (within 30 minutes) to 80°C. It is stirred for 12 hours at this temperature. It is cooled in an ice bath to 0°C, and a mixture of 150 ml of ethanol/20 ml of water is added. Then, it is stirred for 30 minutes at room temperature. It is evaporated to dryness in a vacuum and the residue is chromatographed on silica gel (mobile solvent = ethanol/conc. aqu. ammonia = 10/1) . After concentration by evaporation of the main fractions, 31.71 g (91% of theory) of a yellowish oil is obtained.

Analysis (relative to the anhydrous substance) : Cld: C 55.98 H 9.39 N 18.65 Fnd: C 55.91 H 9.43 N 18.59 b) 10- (2-Carboxyethyl) -1,4,7 , 10-tetraazacyclododecane 46.32 g (825.6 mmol) of potassium hydroxide is added to 31.0 g (103.2 mmol) of the title compound of example la in 150 ml of ethanol/150 ml of water and refluxed for 12 hours. It is cooled in an ice bath to 0°C. It is adjusted with 6N hydrochloric acid to pH 6 and then concentrated by evaporation in a vacuum. The residue is extracted with a mixture of 300 ml of methanol/50 ml of methylene chloride and filtered off from potassium chloride. The filtrate is concentrated by evaporation in a vacuum and purified on a reversed-phase column (RP 18/mobile solvent: gradient of tetrahydrofuran/water) .

Yield: 23.02 g (87% of theory) of a yellowish, viscous oil, which solidifies after a short time Analysis (relative to the anhydrous substance) : Cld: C 56.23 H 9.44 N 21.86 Fnd: C 56.17 H 9.51 N 21.83 Example 2 10- (2-Cyanoethyl) -1, 4 ,7 , 10-tetraazacyclododecane 15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1, 4 , 7 , 10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to room temperature. 9.24 g (174.15 mmol) of acrylic acid nitrile is instilled under a nitrogen atmosphere and heated slowly to 75 °C. It is stirred for 9 hours at this temperature. It is cooled to room temperature and a mixture of 120 ml of methanol/30 ml of water is added. It is stirred for 10 minutes at room temperature. Then, 13.93 g (348.3 mmol) of sodium hydroxide is added and it is stirred for 24 hours at 40 °C. It is evaporated to dryness in a vacuum and the residue is extracted 3 times with hot toluene (80°C) . The organic phase is dried on potassium hydroxide and concentrated by evaporation in a vacuum.

Yield: 23.28 g (89% of theory) of a pale yellow oil, which crystallizes with standing.

Analysis (relative to the anhydrous substance) : Cld: C 58.63 H 10.29 N 31.08 Fnd: C 58.57 H 10.34 N 30.96 Example 3 10 - [ (2-Phenyl-2-carboxy) -ethyl] - 1 , 4,7 , 10-tetraazacyclododecane 15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1,4,7,10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to room temperature. 24.55 g (139.32 ol) of 2-phenyl-vinyl acid ethyl ester is instilled under a nitrogen atmosphere and slowly heated to 130 °C. It is stirred for 12 hours at this temperature. It is cooled to room temperature and a mixture of 150 ml of methanol/150 ml of water is added. Then, it is stirred for 30 minutes at room temperature. 52.11 g (928.8 mmol) of potassium hydroxide is added and refluxed for 12 hours. It is cooled in an ice bath to 00C and adjusted with cone, hydrochloric acid to pH 7, then evaporated to dryness. The residue is taken up in a mixture of 250 ml of methanol/50 ml of methylene chloride. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent = methyl-tert-butyl ether/methanol/conc. agu. ammonia = 6/2/1) .

Yield: 28.27 g (76% of theory) of a vitreous solid Analysis (relative to the anhydrous substance) : Cld: C 63.72 H 8.81 N 17.48 Fnd: C 63.64 H 8.93 N 17.37 Example 4 11- (2-Cyanoethyl) -1, 4 ,8 , ll-tetraazacyclotetradecane 13.68 g (114.8 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (99.83 mmol) of 1, 4 , 8 , ll-tetraazacyclotetradecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is - 22 - distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to room temperature. 6.36 g (119.8 mmol) of acrylic acid nitrile is instilled under a nitrogen atmosphere and heated slowly to 75 °C. It is stirred for 9 hours at this temperature. It is cooled to room temperature and a mixture of 120 ml of methanol/30 ml of water is added. It is stirred for 10 minutes at room temperature. Then, 11.98 g (299.5 mmol) of sodium hydroxide is added and it is stirred for 24 hours at 40 °C. It is evaporated to dryness in a vacuum and the residue is extracted 3 times with hot toluene (80°C). The organic phase is dried on potassium hydroxide and concentrated by evaporation in a vacuum.

Yield: 21.75 g (86% of theory) of a pale yellow oil, which crystallizes with standing Analysis (relative to the anhydrous substance) : Cld: C 61.62 H 10.74 N 27.64 Fnd: C 61.53 H 10.84 N 27.52 For example, the compounds listed in the following table are produced analogously. - 23 - Table la Key: Temp. (°C)/Zeit (h) = temp. ( °C) /time (h) Loesungsmittel = solvent Ueberschuss (Aiken) = excess (alkene) Ausbeute (%) = Yield (%) Elementaranalyse = elementary analysis (ber.) = (cld) Temp . (°C) Losungs- Uberschuft Ausbeute R E 1 emen teranalyae Zeit (h) mi 11e 1 (Aiken) (¾) 100 °C 1 , 2 87 C 57, 30 H 9 ,62 N 17,82 (ber ) 12 - c 57,35 H 9.58 N 17,87 120 °C 1 , 3 92 c 4.82 H 8,66 N 15 ,04 (ber. ) 12 h - c 54,73 H 8,71 N 14,97 ( ber. ) (ber. ) 100 °C 1.2 93 c 53.11 H 9.29 N 25.81 (ber. ) 24 h - c 53,20 H 9 ,21 N 25,74 - 24 - Table lb Key; Base/Loesungsmittel = base/solvent Ueberschuss Base (eq.) = excess base (eq Zeit (h) = time (h) Ausbeute (%) = yield (%) Elementaranalyse = elementary analysis Rueckfluss = reflux (ber.) = (cld) <— T a b e 1 1 e lb Base/ Uber schuB Temp . Zeit Auabeute R Lbeunga- Base Elementaranalyse <°C) (h) (S) mittel (oq.) KOH 0 Riickf luil 12 83 C 57,75 H 9,69 N 20, 72 (ber. ) eOH/H20 1 : 1 c 57,68 H 9,78 N 20, 67 KOH 10 Ruckflun 2 79 c ¾9,99 H 8,39 N 19, ¾3 (ber. ) EtOH/H20 1 :1 c Ί9.90 H 8.Ί6 N 19,37 @ KOH 8 Riickflun 12 85 c 63.72 H 8,81 N 17, ¾8 (ber. ) Ma.OH/H20 1 : 1 c 63,65 H 8,87 17,39 KOH 8 50 °C 2Ί 79 c 55.88 H 7,¾5 N 19, 16 (ber. ) MeOH/H20 1 : 1 c 55, 8¾ H 7,52 N 19,08 ^A^, NaOH j 3 RT 2k 89 c 5¾.29 H 10, 35 N 28, 70 ( bar . ) MeOH/H20 Ί : 1 c 5<«,23 H 10,29 N 28,81 - 25 - Reactions with compounds of general formula IV: Example 5 a) Mixture of l- and 4-formamido-10- ( 6-hydroxy-2/2-dimethyl-l,3-dioxepan-5-yl) -l, 4 ,7 , 10-tetraazacyclododecane 15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1, 4 , 7 , 10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is partially distilled off in this way. Then,, 20.1 g (139.32 mmol) of 4 , 4-dimethyl-3 , 5, 8-trioxabicyclo- (5.1.0) -octane is instilled under a nitrogen atmosphere and heated slowly (1 hour) to 130 °C. It is stirred for 12 hours at 120 °C. It is cooled to room temperature and a mixture of 120 ml of methanol/30 ml of water is added. Then, it is stirred for one hour at room temperature. It is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel (mobile solvent = methyl-tert-butyl ether/methanol/aqu. cone. ammonia = 15/5/1) . After concentration by evaporation of the main fractions, 36.39 g (91% of theory) of a pale yellow, viscous oil, which crystallizes with standing, is obtained.

Analysis (relative to the anhydrous substance) : Cld: C 55.79 H 9.36 N 16.27 Fnd: C 55.82 H 9.29 N 16.20 b) 10- ( 6-Hydroxy-2 , 2-dimethyl-l , 3-dioxepan-5-yl) -1,4,7, 10-tetraazacyclododecane 57.0 g (1.02 mol) of potassium hydroxide is added to 35.0 g (101.6 mmol) of the title compound of example 5a in 200 ml of methanol/50 ml of water and refluxed for 5 hours. It is evaporated to dryness in a vacuum and the residue is extracted 3 times with 200 ml of hot (80°C) toluene. The organic phase is dried on potassium hydroxide and concentrated by evaporation in a vacuum.

Yield: 31.5 g (98% of theory) of a pale yellow, viscous oil, which becomes solid with standing Analysis (relative to the anhydrous substance) : Cld: C 56.93 H 10.19 N 17.71 Fnd: C 56.87 H 10.25 N 17.63 Example 6 a) Mixture of 1- and 4-formamido-10- (2-hydroxypropyl) -1/4,7, 10-tetraazacyclododecane 15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1, 4 , 7 , 10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to 0°C. The residue is dissolved in 50 ml of toluene and the solution is fed into an autoclave. 20.23 g (348.3 mmol) of propylene oxide is added and the autoclave is made airtight. Then, it is heated for 24 hours to 100°C. It is evaporated to dryness in a vacuum and the residue is taken up in a mixture of 120 ml of methanol/30 ml of water. Then, it is stirred for one hour at room temperature. It is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. (Mobile solvent = methanol/isopropanol/aqu. cone, ammonia = 10/5/1) . After concentration by evaporation of the main fractions in a vacuum, 26.7 g (89% of theory) of a weak, yellow-colored oil is obtained.

Analysis (relative to the anhydrous substance) : Cld: C 55.79 H 10.14 N 21.69 Fnd: C 55.72 H 10.19 N 21.61 b) 10- (2-Hydroxypropyl) -1,4,7/ 10-tetraazacyclododecane 45.2 g (805.1 mmol) of potassium hydroxide is added to 26.0 g (100.63 mmol) of the title compound of example 6a in 250 ml of water and refluxed for 5 hours. It is evaporated to dryness in a vacuum and the residue is extracted 3 times with 200 ml of hot (80°C) toluene. The organic phase is dried on potassium hydroxide and concentrated by evaporation in a vacuum.

Yield: 22.02 g (95% of theory) of a weak, yellowish oil, which solidifies after a short time Analysis (relative to the anhydrous substance) : Cld: C 57.36 H 11.38 N 24.32 Fnd: C 57.30 H 11.43 N 24.28 Example 7 10-[2-Hydroxy-5-(2,2-dimethyl-l,3-dioxolan-4-yl)-4-oxapentyl] -1 , 4,7, 10-tetraazacyclododecane 15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1, 4 , 7 , 10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to 40°C. 24.04 g (127.7 mmol) of 2 , 2-dimethyl-4- (2 ■ , 31 -epoxy) -propoxy-methyl-l, 3-dioxolane is instilled under a nitrogen atmosphere and heated slowly (within one hour) to 110°C. It is stirred for 12 hours at this temperature. It is cooled to room temperature and a mixture of 120 ml of methanol/30 ml of H20 is added. Then, it is stirred for 30 minutes at room temperature. 65.1 g (1.16 mol) of potassium hydroxide is added and refluxed for 5 hours. Then, it is concentrated by evaporation in a vacuum and the residue is extracted 3 times with 200 ml of hot toluene (80 °C) . The combined organic phases are dried on potassium hydroxide and evaporated to dryness in a vacuum. The residue is chromatographed on silica gel (mobile solvent = - 28 - methanol/water/aqu. cone, ammonia = 8/2/1) . The main fractions are evaporated to dryness, the residue is dissolved in 500 ml of hot toluene. It is filtered off from insolubles (silica gel) and evaporated to dryness.

Yield: 36.41 g (87% of theory) of a pale yellow, viscous oil Analysis (relative to the anhydrous substance) : Cld: C 56.64 H 10.07 N 15.54 Fnd: C 56.53 H 10.13 N 15.49 Example 8 10- [3- (4-Nitrophenoxy) -2 -hydroxy ropyl ] -1,4,7,10-tetraazacyclododecane (as tetrahydrochloride) 15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1 , 4 , 7 , 10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to room temperature. A solution of 29.46 g (150.93 mmol) of (4-nitrophenyl) -2 , 3-epoxypropyl ether in 100 ml of methylene chloride is instilled under a nitrogen atmosphere. Then, it is heated slowly to 120 °C, and the methylene chloride is distilled off (toward the end under reduced pressure) . It is stirred for 12 hours at 120 °C. It is cooled to room temperature and a mixture of 160 ml of methanol/20 ml of water is added. Then, it is stirred for 30 minutes at room temperature. 50 ml of cone, hydrochloric acid is added and refluxed for 12 hours. Then, it is evaporated to dryness in a vacuum. The residue is recrystallized from methanol/ether.

Yield: 48.27 g (81% of theory) of a yellow-colored crystalline powder Analysis (calculated for a Cl-free compound) : Cld: C 55.57 H 7.95 N 19.06 Fnd: C 55.49 H 8.03 N 19.01 Example 9 a) 11- [3- (4-Nitroxyphenoxy) -2-hydroxypropyl] -1,4,8, 11-tetraazacyclotetradecane (as tetrahydrochloride) 13.68 g (114.8 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (99.83 mmol) of 1,4,8,11-tetraazacyclotetradecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to room temperature. A solution of 23.38 g (119.8 mmol) of (4-nitrophenyl) -2 , 3-epoxypropyl ether in 100 ml of methylene chloride is instilled under a nitrogen atmosphere. Then, it is heated slowly to 120 °C, and the methylene chloride is distilled off (toward the end under reduced pressure) . It is stirred for 12 hours at 120 °C. It is cooled to room temperature and a mixture of 150 ml of methanol/20 ml of water is added. Then, it is stirred for 30 minutes at room temperature. 100 ml of cone, hydrochloric acid is added and refluxed for 12 hours. Then, it is evaporated to dryness in a vacuum. The residue is recrystallized from methanol/ether.

Yield: 41.61 g (77% of theory) of a yellowish, crystalline powder.

Analysis (relative to the anhydrous substance) : Cld: C 42.16 H 6.89 N 12.94 CI 26.20 Fnd: C 42.10 H 6.93 N 12.90 Cl 26.08 Example 10 a) Mixture of 1- and 4- and 8-formamido-li- [2-hydroxy-2-(2,2-dimethyl-l, 3-dioxolan-4-yl ) -ethyl]-l,4,8,ll-tetraazacyclotetradecane 13.68 g (114.8 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (99.83 mmol) of 1, 4 , 8 , 11-tetraazacyclotetradecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by - 30 - evaporation under reduced pressure. The residue is cooled to room temperature. 17.27 g (119.8 mmol) of 2- (2 , 2-dimethyl-l, 3-dioxolan-4-yl) -ethylene oxide is instilled under a nitrogen atmosphere and then heated slowly to 130°C. It is stirred for 12 hours at this temperature. It is cooled to 0°C and a mixture of 160 ml of methanol/40 ml of water is added, then it is stirred for 1 hour at room temperature. It is evaporated to dryness in a vacuum and the residue is chromatographed on silica gel (mobile solvent = methyl-tert-butyl ether/methanol/conc. aqu. ammonia = 15/5/1) .

Yield: 33.1 g (89% of theory) of a pale yellow, viscous oil Analysis (relative to the anhydrous substance) : Cld: C 58.04 H 9.74 N 15.04 Fnd: C 58.13 H 9.61 N 14.92 b) 11- [2-Hydroxy-2- (2 , 2-dimethyl-l, 3-dioxolan-4-yl) -ethyl]-l 4/8 11-tetraazacyclotetradecane 39.15 g (698 mmol) of potassium hydroxide is added to 32.0 g (87.22 mmol) of the title compound of example 10a in 200 ml of methanol/100 ml of water and refluxed for 5 hours. It is evaporated to dryness in a vacuum and the residue is extracted 3 times with 200 ml of hot toluene (80 °C) . The organic phase is dried on potassium hydroxide and concentrated by evaporation in a vacuum.

Yield: 28.85 g (96% of theory) of a pale yellow, viscous oil, which solidifies after a short time Analysis (relative to the anhydrous substance) : Cld: C 59.27 H 10.53 N 16.26 Fnd: C 59.18 H 10.61 N 16.17 For example, the compounds listed in the following table are produced analogously. - 31 - Table 2a Key; Zeit (h) = time (h) Loesungsitiittel = solvent Ueberschuss (Epoxid) = excess (epoxide) Ausbeute (%) = yield (%) Elementaranalyse = elementary analysis (ber.) = Cld (Fortsetzung) = (continuation) Ueberschuss (Aiken) = excess (alkene) ϊοπιρ . ( °C ) Losungf Oborachufi Λυ a b ou t o R Elomontora Zoit (h) m i t t c 1 (Epoxid) (.%) 120 °C 1 , 1 91 c 6l ,69 11 0,63 ^-o^ 0 h - c 6 i , 6 i II 0,67 120 "C 1 , 1 90 c 6 ?. , 6 l II 0 , (15 0 c 62, 6Ί 11 0,00 59,90 H 0,'ιδ 8 h CH2C12 59,09 H 0,53 ( Fortsotzung) T o b o 1 1 o 2o Temp. ( C) Loaungs- Ubcrachuli Auabouto E lcino Zeit ( ) niittoi (A Ikon) 1 , 1 93 C 56,93 U 10, n h C 55 , 86 II 10, 1 0 c * V V 59 ,97 Π 10.

U h C 59, II 10 , 1 , 2 07 C 62, 1 Ί H 10, 12 h c 62,03 li 10, - 34 - Table 2b Key: Base/Loesungsntittel = base/solvent Ueberschuss Base (eq.) = excess base (eq. ) Zeit (h) = time (h) Ausbeute (%) = yield (%) Elementaranalyse = elementary analysis Rueckfluss = reflux (ber.) = (cld) (Fortsetzung) = (continuation) Base/ Ub e r schufi Temp . Zcit Ausbeute Lbaungs- Base Eleme (°C) (h) mittol < eq.) KOH 10 nUckf lufi 97 C 56,93 II 10, MeOH/H 0 Ί : 1 C 56 , 00 H 10, NoOH 63,32 H 9, KtOK/Κ,,Ο 5 : 1 63,20 H 9 , NaOH 60 °C 2Ί 98 C 6Ί.25 H 9, EtOH/H20 5; ! C 6Ί, \ 't H 9, KOH 57,21 H 0, EtOH/H 0 8: 1 57, 1'i H 8, ( Fortsotzung ) n b e 1 1 c 2b B os o/ Ubor schuft Temp . Z a I t Ausbeut o Lb sung s - U a a e (°C) ( ) (54) mittol q.) NaOH nUckf lufl 98 C 58, 30 MoOH/ll20 Ί : 1 C 5θ,2'ι KOH 10 Uuclif l li 98 c 61 , 72 E tOlf/H b : 1 C 61 ,67 KOH 10 Ruckflufl 97 C 63 , 6 Ί EtOH/HgO 'ii1 C 63 , 5 k . KOH 30 C ka 93 C 61 , 7'i ,ΕΐΟΗ/Η,,Ο k : 1 C 61 , 66 Reactions with compounds of general formula V: R9-N=C=X Example 11 10- (N-Phenylcarbamoyl) -1,4,7 , 10-tetraazacyclododecane 15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1,4,7, 10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to 0°C. 16.6 g (139.32 mmol) of phenyl isocyanate is instilled under a nitrogen atmosphere and heated slowly to 100 °C. It is stirred for 12 hours at this temperature. It is cooled to room temperature and a mixture of 160 ml of ethanol/40 ml of water is added. Then, it is stirred for 10 minutes at room temperature. Then, 18.58 g (464.4 mmol) of sodium hydroxide is added and it is stirred for 24 hours at 40 °C. It is evaporated to dryness in a vacuum and the residue is taken up in 400 ml of water. The aqueous phase is extracted 5 times with 200 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 = methyl-tert-butyl ether/methanol/conc. aqu. ammonia = 6/3/1) .

Yield: 29.1 g (86% of theory) of a pale yellow solid Analysis (relative to the anhydrous substance) : Cld: C 61.83 H 8.65 N 24.03 Fnd: C 61.71 H 8.72 N 23.94 For example, the compounds listed in the following table are produced analogously. - 38 - Table 3a Key: Zeit (h) = time (h) Loesungsmittel = solvent Ueberschuss (eq. ) (Acyl-Reagenz) = excess (eq.) (acyl reagent) Ausbeute (%) = yield (%) Elementaranalyse = elementary analysis (ber.) = (cld) Temp. ( °C ) Loflunga- Uberachud Auaboute E lamen Z.it (h) mittol , ( A .cyl ,- „Reqajonz ,) (S) ioo 1 ,2 93 C 59,05 H 9,60 2 C 59, 1Ί H 9,53 100 "C 1 , 2 O 65,02 H 7,37 lO C 65 , 11 H , 30' 100 c 1.1 90 57,29 H 7,51 12 (1 57,20 H 7,60 100 °c 87 C 62, 31 H 7,06 ifl h C,I2C12 C 62, 35 II 7,01 - 39 - Table 3b Key: Base/Loesungsmittel = base/solvent Ueberschuss Base (eq.) = excess base (eq.) Zeit (h) = time (h) Ausbeute (%) = yield (%) Elementaranalyse = elementary analysis (ber.) = (cld) T n b o l l o b Ooao/ Ubersc uH Temp. Zoit Auabouto Lbaunga- Uaac Elementa (°C) (h) (S) mittol (eq. ) NaOll 60,57 H 10,50 -o EtOH/H20 ¾ : 1 60, ¾8 H 10,58 NaOll C 66 , 80 II 7 , 97 EtOII/ll_0 8 C 66 , 78 H 7,93 NaOH C 58,60 H 8,20 E tOH/H 0 C 58,63 H 8, 29 NaOH Ί0 2Ί 96 C 63,83 H 7,61 EtOH/H20 8: 1 C .63,78 H 7,55 - 40 Reactions with a compound of general formula VI: Example 12 a) Mixture of 1- and 4-formamido-10- [2- (p-tolylsulfonylamino) -ethyl] -1, 4 ,7 , 10-tetraazacyclododecane 15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1,4,7, 10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to 0°C. A solution of 25.19 g (127.71 mmol) of p-tolylsulfonyl aziridine in 100 ml of toluene is instilled under a nitrogen atmosphere and then stirred for 8 hours at 80 °C. It is evaporated to dryness in a vacuum and the residue is taken up in a mixture of 180 ml of ethanol/30 ml of water. Then, it is stirred for 30 minutes at room temperature. Then, it is evaporated to dryness. The residue is chromatographed on silica gel (mobile solvent = methyl-tert-butyl ester/methanol/conc. aqu. ammonia = 6/2/1) .

Yield: 40.61 g (88% of theory) of a vitreous solid Analysis (relative to the anhydrous substance) : Cld: C 54.38 H 7.86 N 17.62 S 8.06 Fnd: C 54.31 H 7.93 N 17.58 S 7.99 b) 10-[2-(p-Tolylsulfonylamino)-ethyl]-l, 4,7, 10-tetraazacyclododecane 20.12 g (503 mmol) of sodium hydroxide is added to 40.0 g (100.62 mmol) of title compound 9a in 180 ml of ethanol/30 ml of water and refluxed for 12 hours. It is evaporated to dryness and the residue is taken up in 100 ml of water. The pH of the solution is brought to pH 10 by adding 6N hydrochloric acid. Then, it is extracted twice with 250 ml of hot toluene (80 °C) . The organic phase is dried on magnesium sulfate and concentrated by evaporation in a vacuum.

Yield: 36.07 g (97% of theory) of a yellowish, vitreous solid Analysis (relative to the anhydrous substance) : Cld: C 55.26 H 8.46 N 18.95 S 8.68 Fnd: C 55.21 H 8.52 N 18.90 S 8.59 c) Mixture of 1- and 4-formamido-10- [2-(methylsulfonylamino) -ethyl] -1, ,7 , 10-tetraazacyclododecane Analogously to example 12a, methylsulfonyl aziridine can be used instead of p-tolylsulfonyl aziridine.

Yield: 89% of theory Analysis (relative to the anhydrous substance) : Cld: C 44.84 H 8.47 N 21.79 S 9.97 Fnd: C 44.76 H 8.53 N 21.73 S 9.90 d) 10- [2- (methylsulfonylamino) -ethyl] -1,4,7,10-tetraazacyclododecane Analogously to example 12b, the title compound of example 12c can be used instead of title compound 12a.

Yield: 96% of theory Analysis (relative to the anhydrous substance) : Cld: C 45.03 H 9.27 N 23.87 S 10.93 Fnd: C 44.96 H 9.34 N 23.98 S 10.85 - 42 - Reactions with compounds of general formula VII: CH2-CH-K-CH-CH2 w \ / o o Example 13 a) Mixture of the bis-formamides of 1,1 · - (2 , 6-dihydroxy-4-oxa-1, 7-heptyl) -bis- [1,4,7, 10-tetraazacyclododecane 15.9 g (133.5 mmol) of dimethylformamide-dimethylacetal (under nitrogen) is added to 20.0 g (116.1 mmol) of 1, 4 , 7 , 10-tetraazacyclododecane in 200 ml of absolute toluene. It is refluxed slowly and the solvent is distilled off in this way. Then, it is concentrated by evaporation under reduced pressure. The residue is cooled to 40°C. 7.25 g (55.7 mmol) of bis- [2 , 3-epoxypropyl ] -ether is instilled under a nitrogen atmosphere and heated slowly to 120 °C. It is stirred for 24 hours at this temperature. It is cooled to room temperature and a mixture of 200 ml of methanol/100 ml of water is added. Then, it is stirred for one hour at room temperature. It is evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent = methanol/isopropanol/conc. aqu. ammonia = 8/2/1) . Yield: 18.63 g (63% of theory) of a vitreous solid Analysis (relative to the anhydrous substance) : Cld: C 54.32 H 9.50 N 21.11 Fnd: C 54.25 H 9.57 N 21.18 b) 1 , 1 ' - (2 , 6-Dihydroxy-4-oxa-l , 7-heptyl ) -bis- (1,4,7, 10-tetraazacyclododecane) 28.55 g (508.7 mmol) of potassium hydroxide is added to 18.0 g (33.92 mmol) of the title compound of example 13a in 200 ml of methanol/100 ml of water and refluxed for 2 hours. It is evaporated to dryness in a vacuum and the residue is extracted 3 times with 200 ml of hot toluene (80 °C) . The organic phase is dried on potassium hydroxide and concentrated by evaporation in a vacuum. - 43 - Yield: 15.62 g (97% of theory) of a pale yellow, viscous oil, which solidifies with standing.

Analysis (relative to the anhydrous substance) : Cld: C 55.67 H 10.62 N 23.61 Fnd: C 55.61 H 10.68 N 23.56 For example, the compounds listed in the following table are produced analogously. - 44 - Table 4a Key: Zeit (h) = time (h) Loesungsmittel = solvent Equivalent Diepoxid = equivalent diepoxide Ausbeute (%) (bezgl. Diepoxid) = yield (%) (relative to diepoxide) Elementaranalyse = elementary analysis (ber.) = (cld) = phenyl omp. (°C) sungs- Equivolorit Ausboute ( % ) Elemon Zeit (h) ittol Diopoxid ( czgl .Uiopoxid) 120 C , Ί 9 1 55, OU II 9,5 2'i h 55 , 13 II 9,5 120 "C 0 , Ί 60 C 55 ,79 H 9,7 2'i h C 55,71 H 9,7 120 °C 0 , Ί5 59 C 59, 8 H 8, 9 12 li c 59, 31 H 9,0 M; 130 °C 0 , Ί5 c 55,27 H 9,2 12 h c 55,21 H 9, 3 130 "c 0 , Ί9 61 C 57,86 H 0,7 »-< >-< 2h h CH2C12 c 57,79 H 8,6 - 46 - Table 4b Key: Base/Loesungsmittel = base/solvent Ueberschuss Base (eq.) = excess base (eq.) Zeit (h) = time (h) Ausbeute (%) = yield (%) Elementaranalyse = elementary analysis Rueckfluss = reflux (ber.) = (cld) = phenyl Base/ ersc u!) Temp . Zoit Auabeute Loeungs- Dose El ( °C ) ( ) (#) πι i 11 o 1 ( eq. ) OH 15 97 55 , 57 H MeOH/H20 2: 1 55 , 50 H OII 15 Hiickriuft Ί0 6 c 56 , 36 II 1 MoO!l/l!20 2 : 1 c 56 , 1 II KOH 15 niickf lull Ί0 98 C 57 , 1 1 H Mo0ll/H20 2 : 1 c 57 , 0Ί 11 KOH 15 Iluckf lu!i 2'l 97 c 61 , 06 H E tOH/HgO 3 : 1 c 61 ,01 H KOH 15 RiickfluQ Ί8 98 C 59 , 3'" H EtOH/H20 3 : 1 C 59 , 28 H The preceding examples can be repeated with similar 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 from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims (8)

49 103,996/ 3 WHAT IS CLAIMED IS:

1. Process for the production of mono-N-substituted tetraazacyclododecane and tetraazacyclotetradecane derivatives of general formula I: in which: n stands for the numbers 2 or 3; R stands for a β-carboxy alkyl or β-alkoxycarbonyl alkyl, β-cyanide alkyl, β-carboxamido alkyl, β-hydroxy alkyl, aminocarbonyl, aminothiocarbonyl, β-sulfamoylalkyl radical or for a second tetraazacyclododecane or tetraazacyclotetradecane molecule bound by a bis^-hydroxy)-alkylene chain, wherein "alkyl" in β-carboxy alkyl, β-alkoxycarbonyl alkyl, β-cyanide alkyl, and β-carboxamido alkyl stands for -CR^-CHR1-; "amido" in β-carboxamido alkyl stands for CONR5R6; "alkyl" in β-hydroxy alkyl stands for -CHR7CHR8-; "amino" in aminocarbonyl and aminothiocarbonyl stands for X 50 103,996/ 2 (with X in the meaning of an oxygen or sulfur atom), "sulfamoyl" in β-sulfamoylalkyl stands for -NHS02R10; and "alkylene" in bis(P- hydroxy)-alkylene stands for K; R1 stands for a hydrogen atom, a straight-chain or cyclic Ci-C6 alkyl, a phenyl or benzyl group in which the phenyl or benzyl group can be substituted respectively by 1 to 2 chlorine, bromine, nitro, CrC alkoxy, C7-Ci0 aralkoxy and/or CO2R4 radicals, with R4 meaning a hydrogen atom, a Ci.C6 alkyl, phenyl or benzyl group; R2 and R3, independent of one another, each stand for R1 or a CO2R4 group; R5 and R6, independent of one another, each stand for a hydrogen atom, a saturated or unsaturated, straight-chain, branched-chain or cyclic hydrocarbon radical with up to 16 carbon atoms optionally interrupted by 1 to 8 oxygen atoms or 1 to 3 phenylene or phenylenoxy groups, and optionally substituted by 1 to 5 hydroxy groups or 1 to 2 CO2R4 radicals; for phenyl or benzyl radicals optionally substituted by 1 to 3 hydroxy or Ci-C6 alkoxy groups; or R5 and R6 together with the nitrogen atom stand for a saturated or unsaturated, 5- or 6-ring oxygen, sulfur atom or carbonyl group optionally containing another nitrogen, which optionally is substituted by 1 to 3 Ci-C6 alkyl radicals optionally substituted by 1 to 3 hydroxy radicals, and optionally present hydroxy and/or carboxyl groups optionally are protected; R7 and R8, independent of one another, respectively stand for a hydrogen atom, a CrC20 alkyl radical, optionally interrupted by 1 to 10 oxygen atoms, a phenylene, phenylenoxy or phenylenedioxy group, which optionally is substituted by 1 to 3 CrC6 alkyl, 1 to 3 trifluoromethyl, 1 to 7 hydroxy, 1 to 3 CrC7 alkoxy, 1 to 3 C7-C10 aralkoxy, 1 to 2 CO2R4 and/or 1 to 2 phenoxy or phenyl groups optionally substituted by 1 to 2 chlorine, 51 103,996/ 2 bromine, nitro or CrC6 alkoxy radicals, and the optionally present hydroxy radicals optionally are present in protected form; R9 stands for a phenyl, 1 or 2 naphthyl or straight-chain or cyclic CrC6 alkyl group; R10 stands for a Ci-C6 alkyl, -CF3 or a phenyl group optionally substituted by a Ci-C6 alkyl, chlorine, bromine, or nitro radical; K stands for a C0-Ci6 alkylene chain optionally substituted by 1 to 6 hydroxy, 1 to 6 CrC7 hydroxyalkyl, 1 to 8 CrC7 alkoxy, 1 to 8 C7-Ci0 aralkoxy and/or 1 to 2 benzyloxy groups, and optionally interrupted by 1 to 6 oxygen atoms, 1 to 2 phenylene, phenylenoxy or phenylenedioxy groups; and wherein carboxyl and hydroxy groups are present optionally in protected form; characterized in that the compounds of general formula II obtained from 1,4,7,10-tetraazacyclododecane or 1,4,8,11-tetraazacyclotetradecane are reacted with an α,β-unsaturated ester, amide or nitrile, or an epoxide, isocyanate, isothiocyanate, aziridine or a bisepoxide, with or without solvent, at 0-220°C, preferably room temperature to 210°C, within 1 to 48 hours, preferably 5 to 12 hours, optionally at a pressure up to 100 atm; then the thus-obtained reaction mixture, after cooling to -20-80°C, preferably 0-30°C, is mixed with a mixture of water/organic solvent and stirred 52 103,996/ 2 for 0.5-12 hours, preferably 0.5-3 hours at -20°C to room temperature, preferably 0°C to room temperature; then the thus-formed, optionally to be isolated, intermediate products carrying a formyl group on a nitrogen atom are reacted by adding an inorganic base or an acid at 0-150°C, preferably room temperature to 120°C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring, optionally followed by subsequent removal of protecting groups in a way usual in the art, to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride.

2. A process according to claim 1, for the production of compounds of general formula I with R meaning a -A group, R3 in which: R1 stands for a hydrogen atom, a straight-chain or cyclic Cj-C6 alkyl, a phenyl or benzyl group in which the phenyl or benzyl group can be substituted respectively by 1 to 2 chlorine, bromine, 53 103,996/3 nitro, C-C7 alkoxy, C7-C10 aralkoxy and/or C02R4 radicals with R4 meaning a hydrogen atom, a ^-C6 alkyl, phenyl or benzyl group, R2 and R3, independent of one another, each stand for R1 or a C02R4 group, R5 4 / A stands for a CN, C02R or CON radical, in which R5 and R6, independent of one another, each stand for a hydrogen atom, a saturated or unsaturated, straight-chain, branched-chain or cyclic hydrocarbon radical with up to 16 C atoms optionally interrupted by 1 to 8 oxygen atoms or 1 to 3 phenylene or phenylenoxy groups, and optionally substituted by 1 to 5 hydroxy groups or 1 to 2 C02R radicals; for phenyl or benzyl radicals optionally substituted by 1 to 3 hydroxy or C^-C^ alkoxy groups; or R5 and R6 together with the nitrogen atom stand for a saturated, or unsaturated 5- or 6-ring, optionally containing another nitrogen, oxygen, sulfur atom or a carbonyl group, which optionally is substituted by 1 to 3 C,-C6 alkyl radicals optionally substituted by 1 to 3 hydroxy radicals, and optionally present hydroxy and/or carboxyl groups optionally are protected, wherein tetraazatricyclotridecane or tetraazatricyclopentadecane of formula II 54 103,996/2 is reacted with a feedstock of general formula III in which R, R2, R3 and A have the above-indicated meanings, and optionally present hydroxy and/or carboxyl groups are optionally protected, with or without solvent, preferably aprotic solvents, such as, e.g., benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or ether, are used as solvent, at 0°C to 210°C, preferably 50°C to 180°C (and in the case of the higher reaction temperature, the solvent used optionally to dissolve the added feedstock of general formula III was distilled off previously in a vacuum), within 12 to 48, preferably 5 to 12 hours; then the thus obtained reaction mixture is cooled to -20 °C to 80 °C, preferably 0° to 30°C, mixed with a mixture of water/organic solvent, such as, e.g., methanol, ethanol, isopropanol, tetrahydrofuran or dioxane, and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours, at -20°C to room temperature, preferably 0°C to room temperature; then the thus formed — optionally to be isolated — intermediate product carrying a formyl group on a nitrogen atom is reacted by adding an inorganic base such as, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid, such as, e.g., hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at 0°C to 150°C, preferably room temperature to 120°C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring — optionally followed by subsequent removal of protecting groups in a way usual in the art — to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride. 55 103,996/2

3. Process according to claim 1 for the production of compounds of general formula I with R meaning a OH I 8 — CH—CH—R group, in which R7 and R3, independent of one another, respectively stand for a hydrogen atom, a Ο,-Ο^ alkyl radical, optionally interrupted by 1 to 10 oxygen atoms, a phenylene, phenylenoxy or phenylenedioxy group, which optionally is substituted by 1 to 3 alkyl, 1 to 3 trifluoromethyl, 1 to 7 hydroxy, 1 to 3 C^-Cj alkoxy, 1 to 3 C7-C10 aralkoxy, 1 to 2 CO-Jl and/or 1 to 2 phenoxy or phenyl groups optionally substituted by 1 to 2 chlorine, bromine, nitro or ,-C6 alkoxy radicals, and the optionally present hydroxy radicals optionally are present in protected form, wherein tetraazatricyclotridecane or tetraazatricyclopentadecane is reacted with a feedstock of general formula IV 7 8 in which R and R have the above-indicated meaning and wherein optionally present hydroxy and/or carboxyl groups optionally are protected, with or without solvent, preferably aprotic solvents, such as, e.g., benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexane or ether are used as solvent, at 0°C to 220°C, preferably 50°C to 180°C (and in the case of the higher reaction temperature, the solvent optionally used to dissolve the 56 103 ,996/2 added feedstock of general formula IV was previously distilled off in a vacuum) or in an autoclave at an excess pressure of 1 to 100 atm. within 1 to 48 hours, preferably 5 to 12 hours; then the thus obtained reaction mixture is cooled to -20°C to 80 °C, preferably 0°C to 30°C, mixed with a mixture of water/organic solvent, such as, e.g., methanol, ethanol, isopropanol, tetrahydrofuran or dioxane and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours, at -20°C to room temperature, preferably 0°C to room temperature; then the thus formed — optionally to be isolated — intermediate product carrying a formyl group on a nitrogen atom is reacted by adding an inorganic base, such as, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid, such as, e.g., hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at 0°C to 150°C, preferably room temperature to 120°C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring — optionally followed by subsequent removal of the protecting groups in a way usual in the art — to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride. 57 103,996/3

4. Process according to claim 1 for the production of compounds of general formula I with R meaning a -C-NH radical, X in which X means an oxygen or sulfur atom and R9 means a phenyl, 1- or 2-naphthyl or straight-chain or cyclic C,-C6 alkyl group, wherein tetraazatricyclotridecane or tetraazatricyclopenta-decane of formula II is reacted with a feedstock of general formula R9 - N = C = X (V) , 9 . . . in which X and R have the above-indicated meanings, with or without solvent, preferably aprotic solvents, such as, e.g., benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or ether, are used as solvent, at 0°C to 180°C, preferably room temperature to 150°C (and in the case of the higher reaction temperature, the solvent used optionally to dissolve the added feedstock of general formula V was distilled off previously in a vacuum), within 1 to 48 hours, preferably 5 to 12 hours; then the thus obtained reaction mixture is cooled to -20 °C to 80°C, preferably 0° to 30°C, mixed with a mixture of water/organic solvent, such as, e.g., methanol, ethanol, isopropanol, tetrahydrofuran or dioxane, and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours, at -20°C to room temperature, preferably 0°C to room temperature; then the thus formed — optionally to be isolated —intermediate product carrying a formyl group on a nitrogen atom 58 103,996/2 is reacted by adding an inorganic base such as, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid, such as, e.g., hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at 0°c to 150°C, preferably room temperature to 120°C/ within 1 to 72 hours, preferably 6 to 24 hours, with stirring to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride.

5. Process according to claim 1 for the production of compounds of general formula I with R meaning a - (CH2) 2-NH-S02-R10 radical, in which R10 means a ^-C6 alkyl, -CF3 or a phenyl group optionally substituted by a C,-C6 alkyl, chlorine, bromine or nitro radical, wherein tetraazatricyclotridecane or tetraazatricyclopentadecane is reacted with a feedstock of general formula VI in which R10 has the above-indicated meaning, with solvent, preferably aprotic solvents, such as, e.g., benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethyIformamide, hexane or ether, are used as solvent, at 0°C to 180°C, preferably room temperature to 150°C (and in the case of the higher reaction temperature, the solvent used was distilled off previously in a vacuum) , within 1 to 48 hours, preferably 5 to 12 hours; 59 103,996/2 then the thus obtained reaction mixture is cooled to -20 °C to 80 °C, preferably 0° to 30°C, mixed with a mixture of water/organic solvent, such as, e.g., methanol, ethanol, isopropanol, tetrahydrofuran or dioxane, and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours, at -20 °C to room temperature, preferably 0°C to room temperature; then the thus formed — optionally to be isolated — intermediate product carrying a formyl group on a nitrogen atom is reacted by adding an inorganic base such as, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid, such as, e.g., hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at 0°C to 150°C, preferably room temperature to 120°C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride.

6. Process according to claim 1 for the production of compounds of general formula I with R meaning a second 1,4,7,10-tetraazacyclododecane or 1 , 4 , 7 , 10-tetraazacyclotetradecanemolecule bound by a bis (B-hydroxy) -alkylene chain -CH,-CH-K-CH-CH,- I I OH OH in which K means a C0-C16 alkylene chain optionally substituted by 1 to 6 hydroxy, 1 to 6 C^-Cj hydroxyalkyl, 1 to 8 ^-C7 alkoxy, 1 to 8 C7-C10 aralkoxy and/or 1 to 2 benzyloxy groups, and optionally interrupted by l to 6 oxygen atoms, 1 to 2 phenylene, phenylenoxy 60 103,996/1 or phenylenedioxy groups, and the optionally present hydroxy groups are optionally in protected form, wherein tetraazatricyclotridecane or tetraazatricyclopentadecane is reacted with a feedstock of general formula VII CH,-CH-K-CH-CH, (VII) , \ / \ / 2 0 0 in which K has the above-indicated meaning, and optionally present hydroxy groups are optionally protected, with or without solvent, preferably aprbtic solvents, such as, e.g., benzene, toluene, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, hexane or ether, are used as solvent, at 0°C to 220°C, preferably 50°C to 180°C (and in the case of the higher reaction temperature, the solvent used optionally to dissolve the added feedstock of general formula VII was distilled off previously in a vacuum) or in an autoclave at an excess pressure of 1 to 100 atm. within 1 to 48 hours, preferably 5 to 12 hours; then the thus obtained reaction mixture is cooled to -20°C to 80°C, preferably 0° to 30°C, mixed with a mixture of water/organic solvent, such as, e.g., methanol, ethanol, isppropanol, tetrahydrofuran or dioxane, and stirred for 0.5 to 12 hours, preferably 0.5 to 3 hours, at -20°C to room temperature, preferably 0°C to room temperature; then the thus formed — optionally to be isolated — intermediate product carrying a formyl group on a nitrogen atom is reacted by adding an inorganic base such as, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or calcium hydroxide, preferably sodium hydroxide and potassium hydroxide, or a mineral acid, such as, e.g., hydrochloric, sulfuric or hydrobromic acid, preferably hydrochloric acid, at 0°C to 150 °C, preferably room temperature to 120°C, within 1 to 72 hours, preferably 6 to 24 hours, with stirring — optionally followed by subsequent removal of protecting groups in a way usual in the art 61 103,996/ 2 — to obtain the end product of formula I, which can then be isolated in a way known in the art, preferably as hydrochloride.

7. A process according to claim 1, wherein the reaction is performed starting from 1,4,7,10-tetraazacyclododecane or 1,4,8,11 -tetraazacyclotetradecane without isolating the intermediate products of formula II to the compounds of general formula I.

8. Use of the mono-N-substituted tetraazacyclododecane and tetraazacyclotetradecane derivatives of general formula I produced according to claims 1 to 7, for the production of metal complexes for diagnosis and treatment, substantially as described in the specification. for the Applicant: WOLFF, BREGMAN AND GOLLER bv: It .