ZA200507437B

ZA200507437B - Trimeric macrocyclically substituted benzene derivatives

Info

Publication number: ZA200507437B
Application number: ZA200507437A
Authority: ZA
Inventors: Platzek Johannes; Schirmer Heiko; Juan R Harto; Weinmann Hanns-Joachim; Martin Jose Luis; Bjoern Riefke
Original assignee: Schering Ag
Priority date: 2003-02-19
Filing date: 2005-09-15
Publication date: 2007-02-28
Also published as: NO20054291D0; EP1594851A1; NO20054291L; AU2003290032A1; WO2004074267A1; RU2005128834A; DE10307759B3; CA2516467A1; AR043205A1; MXPA05008781A; CN1753878A; KR20050105474A; JP2006514664A; CR7937A; ECSP056026A; AU2003290032B2; BR0318125A

Description

® ® 2U05/07437

Trimeric, Macrocyclically-Substituted Benzene Derivatives

The invention relates to the subjects that are characterized in the claims: new trimeric macrocyclically-substituted triiodine and tribromobenzene derivatives, their production and use as contrast media in x-ray diagnosis and MRT diagnosis.

During the last decade, impressive advances were achieved in imaging diagnosis.

The imaging techniques, such as DAS, CT and MRT, have developed into standard and indispensable tools in diagnosis and interventional radiology and now offer a spatial resolution of less than 1 mm. In addition, the possible applications of these techniques are increased decisively by the use of contrast media. This now wide distribution and acceptance of the contrast media in x-ray diagnosis can be attributed to the introduction of non-ionic monomeric triiodoaromatic compounds in the 1980’s, as well as the isoosmolar dimeric iodoaromatic compounds that were introduced in the 1990°s. By these two compound classes, the frequency of contrast medium-induced side effects was reduced to 2-4% (Bush, W. H., Swanson, D. P.: Acute Reactions to Intravascular :

Contrast Media: Types, Risk Factors, Recognition and Specific Treatment. AJR 157, 1153-1161, 1991. Rydberg, J., Charles, J., Aspelin, P.: Frequency of Late Allergy-Like

Adverse Reactions Following Injection of Intravascular Non-ionic Contrast Media. Acta

Radiologica 39, 219-222, 1998). The use of contrast media in connection with modern imaging techniques now extends from the detection of tumors, for high-resolution vascular visualization, to the quantitative determination of physiological factors such as - permeability or perfusion of organs. The concentration of the x-ray contrast medium

J

(here the iodine atom) is decisive for the contrast and the detection sensitivity. Despite further development of the technology, it was not possible to reduce the concentration or the dose to be administered that is necessary for a medical diagnosis. Thus, in a standard

CT study, 100 g of substance or more is injected per patient.

Although the compatibility of the x-ray contrast media has been improved by the introduction of non-ionic triiodobenzenes, the number of side effects is still always high.

Because of very high study numbers of several million per year in x-ray diagnosis, ten thousand patients are thus affected. These contrast medium-induced side effects extend from slight reactions such as nausea, dizziness, vomiting, and hives up to severe reactions such as bronchiospasms, or renal failure up to reactions such as shock or even death. Fortunately, these severe cases are very rare and are observed at a frequency of only 1/200,000 (Morcos, S. K., Thomsen, H. S.: Adverse Reactions to [odinated

Contrast Media. Eur Radiol 11, 1267-1275, 2001).

The frequency of these side effects, which are also observed as pseudoallergic contrast medium-induced side effects, is, however, increased by about a factor of 3 in atopic patients and by a factor of 5 in patients with a previous history of contrast medium-induced side effects. Asthma increases the risk of severe contrast medium- induced side effects by a factor of 6 in non-ionic contrast media (Thomsen, H. S.,

Morcos, S. K.: Radiographic Contrast Media. BJU 86 (Suppll), 1-10, 2000. Thomsen,

H. S., Dorph, S.: High-Osmolar and Low-Osmolar Contrast Media. An Update on

Frequency of Adverse Drug Reactions. Acta Radiol 34, 205-209, 1993. Katayama, H.,

Yamaguchi, K., Kozuka, T., Takashima, T., Seez, P., Matsuura, K.: Adverse Reactions to Ionic and Non-ionic Contrast Media. Radiology 175, 621-628, 1990. Thomsen, H. S., ‘Bush, Jr., W. H.: Adverse Effects on Contrast Media. Incidence, Prevention and

J :

Management. Drug Safety 19: 313-324, 1998). In these situations for x-ray diagnosis, the examiners in recent years most frequently use non-iodine-containing Gd-chelates instead of the standard triiodoaromatic compounds in computer topography but also in interventional radiology as well as DSA (Gierada, D. S., Bae, K. T.: Gadolinium as CT

Contrast Agent: Assessment in a Porcine Model. Radiology 210, 829-834, 1999.

Spinosa, D. 1, Matsumoto, A. H., Hagspiel, K. D., Angle, J. F., Hartwell, G. D.:

Gadolinium-based Contrast Agents in Angiography and Interventional Radiology. AJR 173; 1403-1409, 1999. Spinosa, D. J., Kaufmann, J. A., Hartwell, G. D. : Gadolinium

Chelates in Angiography and Interventional Radiology: A Useful Alternative to

Iodinated Contrast Media for Angiography. Radiology 223, 319-325, 2002). This is, on the one hand, substantiated by the very good compatibility of the metal chelates that are used in MRT, but also by the known fact that lanthanides are also x-ray-opaque. In comparison to iodine, gadolinium and other lanthanides show a greater absorption than iodine especially at higher voltages/energies of the x-ray radiation, such that, in principle, they are suitable as opacifying elements for x-ray diagnosis (Schmitz, S.,

Wagner, S., Schuhmann-Giampieri, G., Wolf, K. J.: Evaluation of Gadobutrol in a

Rabbit Model as a New Lanthanide Contrast Agent for Computer Tomography. Invest.

Radiol. 30(11): 644-649, 1995).

The above-mentioned Gd-containing chelate compounds originally used in the

MRT are also readily water-soluble and are distinguished by an excellent compatibility.

Compared to the iodine-containing/non-ionic contrast media, the rate of light pseudoallergenic reactions is greatly reduced, the rate of fatal reactions is extremely rare and is indicated with 1/1,000,000 (Runge, V. M.: Safety of Approved MR Contrast “Media for Intravenous Injection. J. Magn Reson Imaging 12, 205-213, 2000). In contrast

J : to other contrast medium-induced side effects, such as, e.g., the renal compatibility, pseudoallergic reactions are more likely independent of the administered dose. Also, the smallest dosages can accordingly already trigger a pseudoallergic reaction.

Desired are substances that combine the advantages of the two chemically entirely different classes of compounds.

The extraordinarily high hydrophilia of the metal chelates suggests a low incompatibility rate. lodoaromatic compounds have a higher lipophilia by a factor of 100-200 (larger distribution coefficient between butanol/water) than metal chelates.

Based on the low substance concentration and the low specific proportion of the imaging metal in the entire molecule, the previously known metal chelates for x-ray diagnosis are not optimal (Albrecht, T., Dawson, P.: Gadolinium-DTPA as X-Ray

Contrast Medium in Clinical Studies. BJR 73, 878-882, 2000). More recent attempts to solve this problem describe the production of metal complex conjugates, in which triiodoaromatic compounds are covalently bonded to an open-chain or macrocyclic metal complex (US 5,324,503, US 5,403,576, WO 93/16375, WO 00/75141, WO 97/01359,

WO 00/71526, US 5,660,814). Because of their low hydrophilia and high viscosity, the latter cannot be administered in adequate concentration and reasonable volumes, however.

The purpose is to produce compounds that have an adequate hydrophilia — comparable to that of Gd-chelates -- and in addition exhibit a high concentration of opacifyving elements. Values that are significantly higher than those in metal chelates, which are approximately 25% (g/g), were desirable. In addition, at a higher concentration, a very good water solubility must be provided. In addition to their good

J ; pharmacological properties, the highly concentrated solutions must also indicate a practical viscosity and a low osmotic pressure.

This object is achieved by this invention. The metal complexes of general formula I according to the invention

Hal

Al A

XX 0, in which

Hal stands for bromine or iodine,

Al stands for the radicals —CONR'-(CH,),-NR*(CO-CHZ'-NH)_-CO-CHZ’K, —CONR'+(CH,) -(CONR’CH,), -CHOH-CH,K, —CH,0-(CH,),-CHOH-CH,K, —CH,-0-(CH,),-NR'-(CO-CHZ'-NH)_-CO-CHZ*K , —CH,-NR'-CO-(CHZ'-NH-CO)_-CHZ*-K ,

A’ has the same meaning as A' or in the case that A! has the meaning first mentioned above can also stand for the radical ~NR'-CO-(NR")m-(CHa),-

NR?-(CO-CHZ'-NH),-CO-CHZ’-K, in which R' and R?, independently of one another, mean a hydrogen atom, a C;-C,-alkyl group or a monohydroxy-C,-C,-alky! group,

Z'and 7°, independently of one another, mean a hydrogen atom or a methyl group,

K stands for a macrocyclic compound of formula [4

COOX g

VY

MW——N N—

COOX

(x

N

COOX

(1a) with X in the meaning of a hydrogen atom or a metal ion equivalent of atomic numbers 20-29, 39, 42, 44 or 57-83, provided that at least two X stand for metal ion equivalents and optionally present free carboxy groups optionally are present as salts of organic and/or inorganic bases or amino acids or amino acid amides, show a very good solubility and a distribution coefficient that is comparable to that of Gd-chelates. In addition, the new compounds have a high specific content of opacifying elements, a low viscosity and osmolality and thus good tolerance/compatibility, so that they are extremely well suited as contrast media for x-ray and MR imaging.

Hal preferably stands for iodine, R' and R? stand for hydrogen and the methyl group, n stands for the number 2, and p stands for the number 1.

Bv way of example, radicals A' are mentioned:

J

-CONH(CH,),.3NHCOCH,;NHCOCH(CH3)-, -CONH(CHa),;sNHCOCH,NHCOCH>-, -CONH(CH,),3NHCOCH,-, -CONH(CH,)2,3NHCOCH(CHj3)-, -CONHCH,CH(OH)CHj>-, -CON(CH3)CH,CH(OH)CH>-, - CH,OCH,CH(OH)CH:-, -CONHCH,CONHCH,CH(OH)CH,-, -CH,NHCOCH-, -CH,NHCOCH(CH;)-, -CH,NHCOCH,NHCOCHj>-, -CH,NHCOCH,NHCOCH(CH3)-, -CH,O(CH2),;NHCOCH;-, -CON(CH,CH,0H(CH;);NHCOCH,-, -CH,0(CH,);N(CH,CH,0H)COCH2-.

By way of example, radicals A? are mentioned: ~NHCOCH;NHCOCH;NHCOCH(CH3)-, ~NHCOCH;NHCOCH;NHCOCH,-, ~NHCOCH,;NHCOCH>-, ~NHCOCH,;NHCOCH(CHj)-, -N(CH;)COCH,NHCOCH;- -NHCONH(CH,),NHCONH,-, : -NHCOCH,N(CH,CH,OH)COCH>-,

® ® : -N(CH;)COCH;N(CH,CH,OH)COCH,-.

The compounds of general formula I according to the invention can be produced according to the process that is known by one skilled in the art, by, for example, a) a triiodo- or tribromoaromatic compound of general formula II

Y'-NHR'

Hal Hal

R'NH-Y' Y2-NHR' (i)

Hal being reacted in a way that is known in the art with a macrocyclic compound of general

Ww

Ol o’'c-8—— N N—w w (i) formula III in which

C*0 stands for a —-COOH- or activated carboxyl group,

W stands for a protective group or a -CH,COOX"* group with X* in the meaning of X or a protective group and —Y'-NR'-CO-B!- stands for the radical A' in the meaning “of =CO-NR'(CH2)s-NR*-(CO-CHZ'-NH)-CO-CHZ?- or ~CHz-0~(CHz)a-NR'+(CO-

CHZ'-NH)m-CO-CHZ*- and Y>-NR'-CO-B!' for Y'-NR'-CO-B' or for the case that Y'-

® 9

NR'-CO-B! has the meaning first mentioned above, the latter also stands for—NR'-CO- (NR ")(CH,)p-NR?*-(CO-CHZ'-NH)-CO-CHZ?-, whereby B' means the radical on the first or second (viewed from K) carbonyl group between ~CO- and K, and Y'or Y? stands for the deficient radical of the linker group that is reduced by one imino group, and then optionally protective group W being removed and the radical CH,COOX being introduced in a way that is known in the art or the protective group that optionally stands for X* being removed and then reacted in a way that is known in the art with a metal oxide or metal salt of an element of atomic numbers 20-29, 39, 42, 44 or 57-83 or b) a triiodo- or tribromoaromatic compound of general formula IV co

Hal Hal c’o c'o

Iv

Hal ™ being reacted in a way that is known in the art with a macrocyclic compound of general oul af

COooX'

R'NH-Y——N N —— “A

COOX' VM) formula V in which ~C*O and X* have the above-mentioned meaning, and -CO-NR'-Y? stands for radical A' in the meaning of -CONR'-(CH,),-(CONR’CHz)m-CH(OH)CH>- and thus Y? is in the meaning of -NR'-(CH;),-(CONR*CHaz)-CH(OH)CHj-, and then the protective . group that optionally stands for X* being removed and then being reacted in a way that is known in the art with a metal oxide or metal salt of an element of atomic numbers 20-29, 39,42, 44 or 57-83 or c) a triiodo- or tribromoaromatic compound of general formula VI

Al

Hal Hal

A' A'

Hal (Vh in which

A

A’ fur einen Rest —CH,-0-(CH,) -CH-CH,- steht, [A! stands for a radical ...] being reacted in a way that is known in the art with a cyclene of general formula VII w'

Ol

H——N N—W'

WwW (Vit) i

® PS 1 2005787437 in which W* stands for a hydrogen atom or a protective group, (after the optionally present protective groups have been removed and then radical -CH,COOX has been introduced in a way that is known in the art) to form a metal complex of general formula I with A in the meaning of radical ~CH,-O-(CH_),-CHOH-CH,- or d) a triiodo- or tribromoaromatic compound of general formula VIII

CH,-Nucleofug

Hal Hal

Nucleofug-CH; CH,-Nucleofug (VII)

Hal [Nucleofug = nucleofuge] in which nucleofuge stands for a nucleofuge group, being reacted in a way that is known in the art with a macrocyclic compound of general w

YY

R'HN-CO-B——N N—Ww

Ww (1X) formula IX in which

R' and W have the above-mentioned meanings, and B? stands for the radical _(CHZ'-NHCO)n-CHZ?- and then being further processed as indicated under a), such that metal complexes of general formula I are obtained with Alin the meaning of radical _CH,-NR'-CO-(CHZ'-NHCO),,-CHZ?, whereby then optionally in the metal complexes,

® ® 12 obtained according to a)-d), of general formula I, still present acid hydrogen atoms are substituted by cations of inorganic or organic bases, amino acids or amino acid amides.

As amino protective groups W, the benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl, fluorenylmethoxycarbonyl, benzyl, formyl, 4methoxybenzyl, 2,2,2- trichloroethoxycarbony!, phthaloyl, 1,2-oxazoline, tosyl, dithiasuccinoyl, allyloxycarbonyl, sulfate, pent-4-enecarbonyl, 2-chloroacetoxymethyl (or ethyl) benzoyl, tetrachlorophthaloyl, and alkyloxycarbony! groups that are familiar to one skilled in the art can be mentioned [Th. W. Greene, P. G. M. Wuts, Protective Groups in Organic

Syntheses, 2nd Ed., John Wiley and Sons (1991), pp. 309 - 385; E. Meinjohanns et al, J.

Chem. Soc. Perkin Trans 1, 1995, 405; U. Ellensik et al, Carbohydrate Research 280, 1996, 251; R. Madsen et al, J. Org. Chem. 60, 1995, 7920; R. R. Schmidt, Tetrahedron

Letters 1995, 5343].

The cleavage of the protective groups is carried out according to the process that is known to one skilled in the art (see, e.g., Wiinsch, Methoden der Org. Chemie [Methods of Organic Chemistry], Houben-Weyl, Vol. XV/1, 4™ Edition 1974, p. 315), for example by hydrolysis, hydrogenolysis, alkaline saponification of esters with alkali in aqueous-alcoholic solution at temperatures from 0°C to 50°C, acidic saponification with mineral acids, or in the case of Boc groups with the aid of trifluoroacetic acid.

Activated carboxyl groups are defined above as those carboxyl groups that are derivatized, such that they facilitate the reaction with an amine. Which groups can be used for activation is known, and reference can be made to, for example, M. and A.

Bodanszky, "The Practice of Peptide Synthesis," Springerverlag 1984. Examples are aducts of carboxylic acid with carbodiimides or activated esters, such as, e.g., " hydroxybenzotriazole ester, acid chloride, N-hydroxysuccinimide ester,

® ® 13

F F oO NO, cor mo, <a pr , cont] , cor)

FF 0 NO, und $7 —COrN, .N [and] 4-Nitrophenyl ester and N-hydroxysuccinimide ester are preferred.

The activated esters of the above-described compounds are produced as known to one skilled in the art. Also, the reaction with correspondingly derivatized esters of N- hydroxysuccinimide, such as, for example: 0] o, .

Ha” N( “N

Oo 0 is possible (Hal = halogen).

In general, all commonly used activation methods for carboxylic acids that are known in the prior art can be used for this purpose. The activation of carboxylic acid is carried out according to commonly used methods. Examples of suitable activating reagents are dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide-hydrochloride (EDC), benzotriazol-1-yloxytris(dimethylamino)- phosphoniumhexafluorophosphate (BOP) and O-(benzotriazol-1-yl)-1,1,3,3- tetramethy luroniumhexatluorophosphate (HBTU), preferably DCC. Also, the addition

® ® 14 of O-nucleophilic catalysts, such as, e.g., N-hydroxysuccinimide (NHS) or N- hydroxybenzotriazole, is possible.

Advantageously used as nucleofuges are the radicals:

F,Cl,Br,l, —OTs, —OMs, OH,

F F

AN

—0 Foo —o—( J. LNG )g \

F F 0

NO, © 3) | {

NO, ©

If X stands for an acid protective group, lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, and bis-(p-nitrophenyl)-methyl group, as well as trialkylsilyl groups, are suitable.

The t-butyl group and the benzyl group are preferred.

The cleavage of the protective groups is carried out according to the process that is known to one skilled in the art (see, e.g., Wiinsch, Methoden der Org. Chemie,

Houben-Weyl, Volume XV/1, 4" Edition 1974, p. 315), for example, by hydrolysis, hydrogenolysis, alkaline saponification of esters in aqueous-alcoholic solution at temperatures of 0°C to 50°C, acidic saponification with mineral acids or in the case of tert-butyl esters with the aid of trifluoroacetic acid (Protective Groups in Organic

Claims

® ® 111 Claims

1. Metal complexes of general formula I Hal Al A XX Hal on. in which Hal stands for bromine or iodine, Al stands for the radicals —CONR'-(CH,),-NR*-(CO-CHZ'-NH)_-CO-CHZ"K, —CONR'-(CH,),{(CONR’CH,), -CHOH-CH,K, —CH,0+(CH,),-CHOH-CH,K, —CH,-0-(CH,),-NR'-(CO-CHZ'-NH)_-CO-CHZ*K , —CH,-NR'-CO-(CHZ'-NH-CO)_-CHZ*K , A’ has the same meaning as A' or, in the case that A' has the meaning first mentioned above, can also stand for the radical -NR'-CO-(NR")-(CHa),- NR?-(CO-CHZ'-NH)n-CO-CHZ?-K, in which R' and R?, independently of one another, mean a hydrogen atom, a C,-C;-alkyl group or a monohydroxy-C-C;-alkyl group, Z' and Z’, independently of one another, mean a hydrogen atom or a methyl group, n means the numbers 2-4, m means the numbers 0 or 1 and p means the numbers 1-4,

® ® 112 K stands for a macrocyclic compound of formula I COOX @ a NY A — N—— COOX (al N COOX (1a) with X in the meaning of a hydrogen atom or a metal ion equivalent of atomic numbers 20-29, 39, 42, 44 or 57-83, provided that at least two X stand for metal ion equivalents and optionally present free carboxy groups optionally are present as salts of organic and/or inorganic bases or amino acids or amino acid amides.

2. Metal complexes according to claim 1, characterized in that A! stands for a group: -CONH(CH:),.;NHCOCH,NHCOCH(CH3)-, -CONH(CH.,);.;3NHCOCH,NHCOCH;-, -CONH(CH,).sNHCOCH;-, -CONH(CHa3),.;NHCOCH(CH3)-, -CONHCH,CH(OH)CHa-, -CON(CH;)CH.CH(OH)CHa,-, - CH,OCH,CH(OH)CHj>-, -CONHCH>CONHCH,CH(OH)CH,-, -CH,NHCOCHo>-,

® PY 113 -CH;NHCOCH(CHj3)-, -CH:2NHCOCH,NHCOCH;-, -CH,NHCOCH,;NHCOCH(CH3)-, -CH,0O(CH,);NHCOCH,-, -CON(CH,CH,OH(CH;);NHCOCHg;-, -CH,O(CH;),N(CH,CH,OH)COCH,;-.

3. Metal complexes according to claim 1, wherein A’ stands for a -NHCOCH;NHCOCH,NHCOCH(CHj3)-, -NHCOCH;NHCOCH,NHCOCH;-, -NHCOCH,;NHCOCH,-, ~NHCOCH;NHCOCH(CH;)-, -N(CH3)COCH:NHCOCH,-, -NHCONH(CH;),NHCONH,-, -NHCOCH;N(CH,CH,OH)COCH;-, -N(CH;3)COCH,N(CH>CH;0OH)COCH,-.

4. Metal complexes according to claim 1, wherein X stands for a metal ion equivalent of atomic numbers 21-29, 42, 44, or 58-70.

5. Metal complexes according to claim 4, wherein X stands for a metal ion equivalent of the ions gadolinium(IIIl), dysprosium(III), europium(lII), iron(II) or manganese(II).

® PY 114

6. Pharmaceutical agents that contain at least one metal complex of general formula I according to claim 1, optionally with the additives that are commonly used in galenicals.

7. Use of at least one metal complex according to claim 1 for the production of agents for x-ray diagnosis.

8. Use of at least one metal complex according to claim 4 for the production of agents for MRT diagnosis.

9. Pharmaceutical agents that each contain a metal complex according to claims 1 and 4 in a molar ratio of 2000:1 to 1:1, preferably 49:1 to 4:1.

10. Pharmaceutical agents according to claim 6, wherein the metal complex(es) dissolved or suspended in water or physiological salt solution is (are) present at a concentration of 0.001 to 1 mol/l.

11. Use of at least one metal complex according to claim 1 for the production of agents for x-ray diagnosis and MR diagnosis of cerebral infarctions and tumors of the liver or space-occupying processes in the liver as well as tumors of the abdomen (including the kidneys) and the muscle-skeleton system and especially advantageously, the compounds can be used for the visualization of blood vessels after intraarterial and also intravenous injection.

12. Process for the production of the metal complexes of general formula I according to claim 1, wherein a) a trilodo- or tribromoaromatic compound of general formula II

® C 115 Y'-NHR' Hal Hal TOC

Hal bo is reacted in a way that is known in the art with a macrocyclic compound of general w O'C-B— N N—w (a L (Hn formula III in which

C*O stands for a -COOH- or activated carboxy! group,

W stands for a protective group or a —~CH,COOX* group with X* in the meaning of X or a protective group and ~Y''NR'-CO-B'- stands for the radical A' in the meaning of ~CO-NR'-(CHa)y-NR*-(CO-CHZ!-NH)-CO-CHZ?- or -CH,-O-(CHy)a-NR'-(CO- CHZ'-NH)p-CO-CHZ2- and Y*-NR'-CO-B! for Y'-NR'-CO-B' or for the case that Y'- NR'-CO-B' has the meaning first mentioned above, the latter also stands for-NR'-CO- (NRY)m(CHa2)p-NR?*-(CO-CHZ'-NH)-CO-CHZ?-, whereby B' means the radical on the first or second (viewed from K) carbonyl! group between —CO- and K, and Y'or Y? stands for the deficient radical of the linker group that is reduced by one imino group, ‘and then optionally protective group W is removed and the radical CH,COOX is introduced in a wav that is known in the art or the protective group that optionally stands

® ® 116 for X* is removed and then reacted in a way that is known in the art with a metal oxide or metal salt of an element of atomic numbers 20-29, 39, 42.44 or 57-83 or b) a tritodo- or tribromoaromatic compound of general formula [V c’o Hal Hal co co Iv Hal ™ is reacted in a way that is known in the art with a macrocyclic compound of general ou af COOX R'NH-Y——N N—— COOoX' Vv) formula V in which —C*0O and X* have the above-mentioned meaning and ~CO-NR'-Y? stands for radical A! in the meaning of -CONR'-(CH;),-(CONR*CH2)m-CH(OH)CH,- and thus Y’ is in the meaning of -NR'~(CH,),-(CONR’CH,)n-CH(OH)CHo-, and then the protective group that optionally stands for X‘is removed and then is reacted in a way that is known in the art with a metal oxide or metal salt of an element of atomic numbers 20-29, 39, 42, 44 or 57-83 or

® ® 117 Cc) a triiodo- or tribromoaromatic compound of general formula VI Al Hal Hal A’ A' Hal (VI) in which . 2 A" stands for a radical —CH,-0-(CH,),-CH-CH,- is reacted in a way that is known in the art with a cyclene of general formula VII TV Gl "H—N N—wWwW' Ww vi in which W* stands for a hydrogen atom or a protective group, after the optionally present protective groups have been removed and then radical ~-CH.COOX has been introduced in a way that is known in the art, to form a metal complex of general formula I with A' in the meaning of radical ~CH,-O-(CH,),-CHOH-CH-- or

® ® 118 d) a triiodo- or tribromoaromatic compound of general formula VIII CH,-Nucleofug Hal Hal Nucleofug-CH; CH,-Nucleofug ol (Vi) [Nucleofug = nucleofuge] in which nucleofuge stands for a nucleofuge group, is reacted in a way that 1s known in the art with a macrocyclic compound of general WwW R'HN-CO-B>——N N—W (Ln) L (1X) formula IX in which R! and W have the above-mentioned meanings, and B? stands for the radical —(CHZ'-NHCO)n-CHZ- and then is further processed as indicated under a), such that metal complexes of general formula I are obtained with A' in the meaning of radical ~CH;-NR'-CO-(CHZ'-NHCO)p-CHZ?, whereby then optionally in the metal complexes, obtained according to a)-d), of general formula I, still present acid hydrogen atoms are substituted by cations of inorganic or organic bases, amino acids or amino acid amides.

13. Process for the production of the pharmaceutical agents according to claim 6, wherein the complex compound that is dissolved or suspended in water or physiological

/ PCT/EP2003/014149 et LU 119 salt solution, optionally with the additives that are commonly used in galenicals, is brought into a suitable form for enteral or parenteral administration.

14. A substance or composition for use in a method of x-ray diagnosis, wherein said substance or composition comprises at least one metal complex according to claim 1.

15. A substance or composition for use in a method of MRT diagnosis, wherein said substance or composition comprises at least one metal complex according to claim 4.

16. A substance or composition for use in a method for x-ray diagnosis and MR diagnosis of cerebral infarctions and tumors of the liver or space-occupying processes in the liver as well as tumors of the abdomen (including the kidneys) and the muscle-skeleton system, said substance or composition comprising at least one metal complex according to claim 1, and wherein said substance or composition can be used for the visualization of blood vessels after intraarterial and also intravenous injection.

17. A metal complex according to any one of claims 1 to 5, substantially as herein described and illustrated.

18. An agent according to any one of claims 6, 9 or 10, substantially as herein described and illustrated.

19. Use according to any one of claims 7, 8 or 11, substantially as herein described and illustrated.

20. A process according to claim 12, substantially as herein described and illustrated. AMENDED SHEET }

Co PCT/EP2003/014149 ¢ 120

21. A process according to claim 13, substantially as herein described and illustrated.

22. A substance or composition for use in a method of diagnosis according to any one of claims 14 to 16, substantially as herein described and illustrated.

23. A new metal complex, a new pharmaceutical agent, a new use of a metal complex as claimed in claim 1, a new process for the production of a metal complex, a new use for the production of a pharmaceutical agent, or a substance or composition for a new use in a method of diagnosis, substantially as herein described. AMENDED SHEET