GB2368843A - Non-porphyrin multipurpose contrast agents - Google Patents

Abstract

Compounds (see Fig. 2) comprising a nitrogen-containing heterocyclic ring system covalently bonded to a carbocyclic or heterocyclic ring system by a direct link or optionally substituted linking agent. The ring systems and linking agent may be substituted by metal chelating structures which allow labelling of the compound by complexation with metal ions such as gadolinium ions. The compounds may be used in pharmaceutical compositions which are useful for therapeutic and/or diagnostic applications including nuclear scintigraphy and magnetic resonance imaging and may be used as multipurpose contrast agents for the identification and visualisation of necrosis.

Description

FIELD OF THE INVENTION The present invention relates to a novel class of nonporphyrin labeled compounds useful as tools in biochemical, biomedical and medical applications. In particular, the present invention concerns (1) the use of these novel compounds or pharmaceutically acceptable salts and formulations thereof in therapeutic and/or diagnostic applications comprising Nuclear Scintigraphy (NS) aided and Magnetic Resonance Imaging (MRI) aided applications, which among other applications comprise the use of the novel compounds as contrast agents, in particular multipurpose agents useful for identification and visualisation of diseases, organs and/or systems, comprising the identification and visualisation of necrosis and necrosis related diseases including myocardial and cerebral infarction; (2) the methods to provide the compounds; (3) the methods to provide reactive intermediates. BACKGROUND OF THE INVENTION We were the first to discover that certain (metallo) porphyrins and derivatives thereof, such as the mesoporphyrin derivative Gadophrin-2, allow visualisation of necrotic tissue (ref. 14). Originally, tumor seeking abilities were assigned to these porphyrin compounds. However, this belief turned out to be a misconception. Indeed, if no distinction is made between viable and necrotic tumor components as done previously by others, such compounds are seemingly"taken up"by the tumor. We provided abundant experimental evidence, most of which has already been published, that proves that only the presence of necrotic tissue causes this so-called"uptake". While lesions (tumors) lacking necrotic tissue do not show any"uptake", tumor nonrelated necrosis, such as for example occurring after ischemic (infarction) or chemical (ethanol) injury, does show this so-called "uptake". Hence, these porphyrin compounds and their paramagnetic metal labeled derivatives must be characterized as"necrosis seeking"or as"necrosis avid contrast agents (NACA)"[ref1-3], a view that opened up new possibilities and applications [ref4-7].

Recently, we disclosed (patent application WO 00/09169) a class of labeled non-porphyrin compounds which are, for example, applicable as diagnostics in MRI imaging or nuclear medicine.

Moreover, these compounds exhibit, akin to some porphyrin based agents, a unique targetabillity to necrotic tissues. Hence, they are also useful to visualize myocardial infarctions and other pathologies involving necrosis. This was exemplified by a bis-DTPA pamoic acid derivative, whose gadolinium complex (referred to as EC-111-60) and 99mTc complex in vivo visualization and identitication of diseases involving necrosis. Compounds exhibiting this unique mode of intrinsic targetability should be clearly distinguished from spurious necrosis specific compounds, i. e. those only provoking nonspecific contrast enhancement in necrosis.

It has been mentioned that low molecular wheight paramagnetic gadolinium chelate complexes, such as for example commercially available Gd-DTPA (gadopentetate dimeglumine salt, Magnevist@), Gd-DTPA-BMA (Gd-DTPA-bis-methy) amide, Omniscan@) and the cylcen derivative Gd-DOTA (gadoterate megiumine, Dotarem@), can be used for visualizing myocardial infarction.

These compounds are known to rapidly (10 minutes) diffuse after i. v. administration from the plasma into a larger interstitial compartments. Hence, it is not suprising that in case of for example mycardial infarction these compounds enhance both the ischemic and necrotic myocardium, which jointly constitute an enlarged interstitial space accessible for diffusion. Since ischemia does not necessarily involves necrosis, the injured zones are often much larger than the necrotic zones.

Because only the precise location and the dimensions of the necrosis are of clinical importance, it should be obvious that imaging of the entire injured myocardium is only of limited use. Even for this purpose the use of those spurious"necrosis specific"compounds can be problematic as the timing of postcontrast imaging will be always critical. The latter can be attributed to the fact that these gadolinium chelate, well-known for their rapid body clearance, are not retained due to interaction with necrotic tissue so that imaging is predomantly affected by a combination of body clearance and unpredictable diffusion dynamics, comprising diffusion into and clearance from the injured myocardium. Consequently, inaccurate enhancement of mycardial infarction will be observed, rendering unequivocal diagnosis impossible.

Another type of disease specific agents comprises for example conjugates whereby a gadolinium chelate (e. g. Gd-DTPA) is covalently linked to an antibody raised against a disease related antigen. Although such conjugates may be used for some in vitro applications, it is amply documented that their in vivo performance is extremely poor, mainly due to fast clearace from the plasma by the reticuir endothelial system shortly after intraveneous administration. Accordingly, because these agents are not in vivo effective, one may consider them as spurios disease specific agents.

Decisive proof for considering a compound to be a necrosis avid contrast agent, can be obtained using animal models with induced necrosis by juxtaposing the in vivo MRI images with corresponding post mortem macroscopy (optionally after TCC viability staining). In case of truely necrosis avid agents the MAl aided dilineation of the necrotic zone should match the post mortem histologic identification of necrosis.

Independent from our discovery, an application (DE197 44003A 1, US6083479) was recently published, disclosing derivatives of the azacyclic compounds cyclen (1,4, 7,10 tetraazacyclododecane), pentacyclen (1,4, 7,10, 13-pentaazacyclopentadecane) and hexacyclen (1,4, 7,10, 13, 16-hexaazacyclooctadecane) useful for"Infarkt-und Necroseimaging".

At present, nothing is known about the mechanism of action or about the essential structural requirements necessary to visualize necrosis. This holds true for the porphyrin derivatives, the non-porphyrin compounds (as disclosed in patent application WO 00/09169) and the cyclen based compounds (as disclosed in patent application DE19744003 and equivalent US6083479). Indeed, with regard to the porphyrin derivatives we demonstrated that not all paramagnetic metal derivatives exhibit necrosis seeking abilities [ref9]. Consequently, the porphyrin skeleton as such provides no clues. In a recent paper, Hofman et al [ref10] propose that the tumoral necrosis avid porperties of the porphyrin derivative Gadophrin-2 (a bis-gadopentetic acid mesoporphyrin derivative) may be attributed to a serum albumin-binding mechanism. This explanation is questionable. Firstly, their assumption that serum albumin is the sole and only"tumoral component"that binds the porphyrin derivative is poorly documented and based on incomplete and inadequate analysis (e. g. binding studies performed on proteins denatured by electrophoretic and staining procedures). Secondly, it has been demonstrated [ref11] that a novel non-aromatic low molecular weight blood-pool MRI agent (code-named MP-2269; Mallinckrodt, Inc., USA) which features strong albumin binding [ref12, 13] does not exhibit necrosis seeking abilities. Hence, albumin binding does not explain why certain porphyrin derivatives exhibit necrosis seeking abilities, it also does not provide any clues for identifying compounds as such.

Present invention identifies a new class of nonporphyrin compounds which were obtainable from the result of extensive research and experimentation, involving synthesis and screening of compounds, has been identified. Compounds of this new class are in particular suitable for MRI and NS imaging. Among other useful characteristics the novel compounds exhibit intrinsic abilities to target diseases, such as for example necrosis and related pathologies. This was an unpredictable and surprising result, because (1) the novel compounds are structurally different from both the cyclen based compounds (DE19744003A1, US6083479) and the nonporphyrin compounds having a phenyl based structure (WO 00/09169) and (2) because neither the structural requirements nor the mechanism by which such compounds render their ability to visualize necrosis are known.

It is well-known that metallo-porphyrins and paramagnetic metal labeled porphyrin derivatives suffer from serious drawbacks, such as toxicity in combination with unfavorable therapeutic indices (in particular applying to metallo mesotetraphenyl porphyrins), potential interactions with the well regulated porphyrin metabolism, unwanted discoloration of skin, induction of prolonged photosensitivity, injectable solutions are densly coloured even at very low concentration, and so on.

The nonporphyrin compounds disclosed in WO 00/09169 are clearly superior to the above mentioned porphyrins as they are free of the major drawbacks of the porphyrins. However, they also exhibit some shortcommings highly concentrated solutions are not colourless, during longterm storage slight but significant discoloration of preparations may occur, despite the relatively high LD50 value significant side effects (microscopic level) were observed in some animals (e. g. myocarditis) which received a intraveneous bolus injection ouf 1000/mol Gd/kg body weight.

In view of the prevalence of cerebral and myocardial infarction and of other necrosis related phenomena, It would be of great importance to have contrast agents, in particular multipurpose contrast agents, which are in vivo effective and are useful for identification and localisation of pathological as well as therapeutical necrosis but which do not suffer from the above mentioned drawbacks and shortcommings involving the use of especially the porphyrin derivatives. The present invention provides compounds and methods free of the mentioned drawbacks but having the useful advantages. cerebral General background related to necrosis avid agents is described, for example, in:

[ref1] Ni Y, Marchal G, Yu J, Lukito G, Petr C, Wevers M, Baert AL, Ebert W, Hilger CS, Maier FK, Semmler W : Localization of metalloporphyrin induced"specific"enhancement in experimental liver tumors : a comparison between MRI, microangiographic and histologic findings. Acad Radial 1995 ; 2 : 687-699.

[ref2] Ni Y, Marchal G, Herijgers P, Flameng W, Petr C, Hilger CS, Ebert W, Maier FK, Semmier W, Baert AL : Paramagnetic metalloporphyrins : from enhancers for malignant tumors to markers of myocardial infarcts.

Acad Radio 1996 ; 3 (8) : S395-397.

[ref3] Ni Y, Petr C, Miao Y, Yu J, Cresens E, Adriaens P, Bosmans H, Semmler W, Marchal G : Magnetic resonance imaging-histomorphologic correlation studies on paramagnetic metalloporphyrins in rat models of necrosis. Invest Radial 1997 ; 32 (12) : 770-779.

[ref4] Marchal G, Ni Y, Herijgers P, Flameng W, Petr C, Bosmans H, Yu J, Ebert W, Hilger C-S, Pfefferer D, Semmier W, Baert AL: Paramagnetic metalloporphyrins : infarct avid contrast agents for diagnosis of acute myocardial infarction by magnetic resonance imaging. Eur Radiol 1996 ; 6: 2-8.

[ref5] Herijgers P, Laycock SK, Ni Y, Marchal G, Bogaert J, Bosmans H, Petre C, Flameng W. Localization and determination of infarct size by Gd-mesoporphyrin enhanced MRI in dogs. Int. J. Cardiac Imaging 1997; 13: 499-507.

[ref6] Ni Y, Pislaru C, Bosmans H, Pislaru S, Miao Y, Van de Werf F, Semmler W, Baert AL, Marchal G : Validation of intracoronary delivery of metalloporphyrin as an in vivo"histochemical staining"for myocardial infarction with MR imaging. Acad Radiolne 1998 ; 5 (Suppi 1) : S37-41.

[ref7] Pislaru S, Ni Y, Pislaru C, Bosmans H, Miao Y, Bogaert J, Semmler W, Marchal G, Van de werf F.

Noninvasive measurements of infarct size after thrombolysis with a necrosis-avid MRI contrast agent.

Circulation 1999,99 (5): 690-696.

[ref8] Ni Y, Cresens E, Adriaens P, Miao Y, Verbeke K, Dymarkoski S, Verbruggen A, Marchal G. Necrosis avid contrast agents: introducing nonporphyrin species. Acad Radiol 2000 (in press).

[ref9] Ni Y, Miao Y, Cresens E, Adriaens P, Yu J, Semmler W, Marchal G. Paramagnetic metalloporphyrins : there exist necrosis-avid and non-avid species. In"Proc. of ih Annual Meeting for ISMRM, 1999, Philadelphia, Penn. , USA., # 346.

[ref10] Hofmann B, Bogdanov A, Marecos E, Ebert W, Semmler W, Weissleder R. Mechanism of Gadophrin-2 accumulation in tumor necrosis. JMRI 1999; 9: 336-41.

[ref11] Ni Y, Adzamli K, Miao Y, Cresens E, Yu J, Periasamy MP, Adams MD, Marchal G (submitted for publication to Invest. Radios.) mi contrast enhencement of necrosis by MP-2269 and Gadophrin-2 in A Rat Model of Liver Infarction [ref12] Adzamli K, Spiller M, Koenig SH. NMRD assessment of the interaction of MP-2269 with albumin. in "Proc. of 5th Annual Meeting for ISMRM, 1997, Vancouver BC, Canada, #1574.

[ref13] Wallace RA, Haar JP, Miller DB, Woulfe SR, Pelta JA, Galen KP, Hynes MR, Adzamli K. Synthesis and preliminary evaluation of MP-2269: a novel, nonaromatic small-molecule blood-pool MR contrast agent.

Magn Reson Med 1998; 40: 733-9.

[ref14] Marchal GJF and NI Y. The use of porphyrin-complex or expanded porphyrin-complex compounds as localization diagnosticum for infaction or necrosis. WO95312119. SUMMARY OF THE INVENTION In accordance with a first aspect of the present invention compounds are provided comprising the following structure: (formula 1)

wherein: - L represents a direct link or an optionally substituted linking agent (Li), which links a ring system A with a ring system B by covalent bonding; - the ring system A comprises Z1, which represents the atoms necessary to complete a substituted or unsubstituted unsaturated or partially saturated monocyclic or polycyclic carbocyclic or heterocyclic ring system around the S1 substituted nitrogen atom; - the ring system B comprises Z2, which represents the atoms necessary to complete a substituted or unsubstituted unsaturated, partially saturated or aromatic monocyclic or polycyclic carbocyclic or heterocyclic ring system around the X atom. This X atom may represent a carbon atom or a S2 substituted nitrogen atom; - the substituents S1 and S2 may represent, independently from each other, a hydrogen atom or a saturated or partially unsaturated alkyl, aryl or aralkyl chain optionally comprising one or more heteroatoms and optionally substituted by functional groups or atoms (such as for example oxo, hydroxy, mercapto, amino and the like) ; - if L is not in the meaning of a direct bond, then L refers to an optionally substituted linking agent Li; - R1, R2 and R3 are optional substituents (R) of the ring system A, B and linking agent, respectively. The indices q, p and r are integers indicating the number of substituents present on the Z1 skeleton, the Z2 skeleton and the linking agent Li, respectively ; - C stands for an optional covalently linked metal cheating structure introduced in the molecule to permit homogeneous or heterogeneous labeling of the compound by complexation with metal ions. C is optional if one or more of the constituting elements (ring system A, ring system B, R1, R2, S1, S2 and/or L) already comprise label (s) such as for example dense atoms and/or radioactive atoms. If such label (s) are not available at least one specific substituent referred to as C should be present. When present on ring system A the cheating structure (s) C are/is referred to as C1. The C-function (s) attached to ring system B is/are indicated as C2. If present as substituent (s) of the linker L, the C-function (s) is/are referred to as C3. Ring system A may bear n C1-functions, ring system B may bear m C2-functions and, if present, the linking agent Li may bear o C-functions ; whereby n, m and p are integers ranging from 0 (absence) to 4 and the sum of n, m and o must be one or larger. In a preferred embodiment of the first aspect of the invention at least one substitunt referred to as C is available. Preferred C-functions comprise organyl and organohetryl groups of the general formula - (K-8) o. i-CA, whereby a cheating agent CA is either directly ( -CA) or via a bivalent

chain P-K-8 connected to the joined ring system A and ring system B of the general formula 1 ; indicates the bond to the joined ring system A and ring system B and 8 indicates the bond of K to molecule portion CA.

According to another preferred embodiment of the first aspect of the invention the non-porphyrin compounds comprising the structural formula 1 bear one or more R substituents of general formula -W, wherein indicates the bond to the joined ring system A and ring system B and W is independently selected from the list comprising: halogens, organyl, organohetryl and/or functional groups including radicals such as oxo (=O), thio (=S) and the like.

In a second aspect, the present invention is directed to homogeneous or heterogeneous labeled compounds according to the first aspect of the present invention, said compounds labeled by chelation with one or more radioactive or non-radioactive metal ions; preferably selected from the list comprising radioactive or non-radioactive ions of an element with atomic number 13,21-32, 3739,42-44, 49,50 or 57-83 such as for example Mn, Fe, Gd, 99mTc, 1111n, 67Ga, 90Y, 188Re, 186Re and Dy. In a third aspect of the present invention the non-porphyrin compounds according to the first or the second aspect of the invention, in vitro, in vivo and/or ex vivo effective and used as such.

In a preferred embodiment of the third aspect of the invention the labeled non-porphyrin compounds comprising the structural formula 1 are pharmaceutically acceptable salts and/or formulations suitable for in vitro, in vivo and/or ex vivo use, comprising the use as diagnostic agent and/or therapeutic agent.

In a more preferred embodiment of the third aspect of the invention the labeled non-porphyrin compounds are pharmaceutically acceptable salts and/or formulations suitable for imaging or imaging aided applications, comprising Mari, NS, MRI aided applications or NS aided applications or the use of the labeled non-porphyrin compounds are pharmaceutically acceptable salts for the manufacturing of imaging agents or imaging aidings agents applications for use in MRI, NS, MRI aided applications or NS aided applications.

In a most preferred embodiment of the third aspect of the invention the labeled non-porphyrin compounds are pharmaceutical acceptable salts and/or formulations suitable for both medical MRI or medical NS imaging as well as their corresponding medical applications. These comprise their use as (1) in vivo effective contrast agents, including multipurpose contrast agents, for visualising and/or identifying organs, parts of organs, systems such as for example the vasculatory, the hepatobiliary and the renal-urinary system, tissues such as for example necrotic tissue, diseases and pathologies such as necrosis and necrosis related pathologies, (2) as contrast agents in the follow up of therapy. The labeled non-porphyrin compounds of present invention may also be pharmaceutically acceptable salts for use in the manufacturing of a both medical MRI or medical NS imaging diagnosticum.

In a fourth aspect of the present invention the labeled non-porphyrin compounds according to the third aspect and its embodiments of the present invention are pharmaceutically acceptable salts and/or formulations for use as contrast agents for MRI or NS aided visualisation and identification of the occurrence and/or evolution of necrosis.

In a preferred embodiment of the fourth aspect of the invention the contrast agents are used in medical applications involving necrosis and necrosis related pathologies, such as for example pathological and therapeutic necrosis caused by pathologic or therapeutically induced ischemia or originating from trauma, radiation and/or chemicals, either being of pathalogical origin or being the result of therapy, including therapeutic ablation, radiotherapy and/or chemotheraphy.

In a more preferred embodiment of the fourth aspect of the invention the contrast agents are used in medical applications involving necrosis and necrosis related pathologies referred to as infarctions, including myocardial and cerebral infarction.

In a fifth aspect of the present invention the novel compounds according to aspects 3 up to 4, are administered, enteral or parenteral, as therapheutic and/or diagnostic agents to the body, optionally at low dose.

In a preferred embodiment of the fifth aspect of the invention the contrast agents are used systemically as diagnostic agents by parenteral administration, including intraveneous injection, at doses lower than 60, umol gadolinium/kg body weight, preferably at doses ranging from10 to 20 , umol gadolinium/kg body weight being still in vivo effective in case of systemic applicatons.

In an other preferred embodiment of the fifth aspect of the invention the contrast agents are used by local administration, including for example intracoronary administration in case of myocardial infarction. Goverened by the kind of application the dose may be lower then 5pmol gadolinium/kg body weight In a sixth aspect of the present invention, the R substituents of the compounds according to the second embodiment of first aspect of the present invention are selected in accordance with an object of the present invention to provide multipurpose contrast agents as referred to in a most preferred embodiment of the third aspect of the invention.

In a preferred embodiment of the sixth aspect of the invention R substituents of the non-porphyrin compounds are selected in such a way that a series or a multitude of series of specific compounds, each embodying the structure of general formula 1, are generated which are qualitatively of the same kind but exhibit gradual quantitative differences with respect to blood clearance (ranging from relatively fast to relatively slow), elimination from the body (predominantly by kidney or shifted to more hepatobiliary secretion), plasma protein binding (from low to high).

In a more preferred embodiment of the sixth aspect of the invention pharmaceutically acceptable salts and/or formulations are prepared comprising either a single in vivo effective specific compound, or a combination of two or more specific compounds, whereby type and relative amounts are governed by the desired medical application.

In a seventh aspect, the present invention is directed to a novel method for obtaining a monoreactive monoanhydride comprising the structural formula 2 via an intermediate which facilitates purification such as for example an intermediate monobenzylester obtained by reacting the corresponding bisanhydride of formula 3 with benzylalcohol and another suitable reagent that reacts with anhydrides such as for example water, ammonia, primary as well as secondary amines, hydrazides and alcohols.

In formula 2 and formula 3; the indices s, t, u and v are numerals, which are independently from each other equal or larger than 1; the organylene group V and the substituents Ux and Uy are as described in the detailed description of the invention.

In an eighth aspect, the present invention is directed to overall methods for obtaining the novel compounds of formula 1. These overall methods may be construed as novel disconnections allowing to select suitable precursor compounds and suitable procedures for combining them under reactive conditions according to single step or a multistep procedures. Prefered precursor compounds may be selected as type A precursors comprising in their structure a skeleton akin to the ring A system of formula 1, type B precursors comprising in their structure a skeleton akin to the ring B system of formula 1 and type L precursors, which comprise structural elements akin to the linking agent L of formula 1 and are suitable for linking a type A compound with a type B compound.

In a more preferred embodiment of the eighth aspect of the invention type A and/or type B and/or type L precursors are selected based on the presence of one or more functional groups and/or substituent (s) which enable the introduction a covalently bound metal cheating moiety referred to as C in formula 1 and as described in the first aspect of the present invention, said precursors comprising in their structure one or more reactive moieties, one or more, optionally protected, functional groups, one or more alkyl-, aralkyl and/or aryl-substituents bearing such reactive moieties and/or such reactive functional groups, so that, optionally after appropriate chemical modification, intermediate compounds become available that enable covalent linking to a type C precursor, said a compound or derivative thereof, which comprises structural elements, optionally becoming available after appropriate chemical modification, to participate in complexation of metal ions; preferably radioactive or non-radioactive ions of an element with atomic number 13,21-32, 37-39,42-44, 49,50 or 57-83.

In a more preferred embodiment of the eighth aspect of the invention, type A precursors are selected from a list of compounds comprising as part of their ring system A an indole skeleton, which bears one or more reactive moieties and/or reactive substituent (s) which enable upon reaction with type C precursors the formation of metal cheating C-moieties, type B precursors are selected from the list of type A precursors or from the list comprising as part of their B ring system a phenol.

In an even more preferred embodiment of the eighth aspect of the invention a precursor compound is obtained by reacting together a type A precursor and a type B precursor, both selected from the above mentioned lists, and a type L precursor.

In a most preferred embodiment of the eighth aspect of the invention this type L precursor is either formaldehyde, methylal or selected from a list of aryl, aralkyl and alkyl aldehydes, which optionally bear one or more reactive moieties and/or substituent (s) which enable upon reaction with type C precursors the formation of metal cheating C-moieties. BRIEF DESCRIPTION OF THE FIGURES The invention is further described by the following nonlimiting examples which refer to the accompanying Figure 1 to Figure 3 short particular of which are given below Figure 1 shows a chart representing the novel approach to obtain monoreactive anhydride bifunctional cheating agents Figure 2 is a representation of a species of the general formula 1 as a bis Gd 3+ chelate, referred to as EC-V-7.

Figure 3 A-E: A-D shows photographs of MRI images obtained in a rat model of experimentally induced reperf used liver infarction (necrosis) before (A) and after i. v. injection (0. 05mmol/kg BW) of EC-V-7; 5 minutes (B) 40 minutes (C) and 24 hour (D) post injection; E shows a photograph of macroscopic histological slice corresponding to the MRI images, obtained after sacrificing the same rat; arrows indicate necrotic liver lobe, S stands for stomach. DETAILED DESCRIPTION OF THE INVENTION The term"organyl group"means as discribed in GLOSSARY OF TERMS USED IN PHYSICAL ORGANIC CHEMISTRY (IUPAC Recommendations 1994) any organic substituent group, regardless of functional type, having one free valence at a carbon atom. The term includes univalent substituent groups having a free valence at for example an acylcarbon.

The term"organohetryl group"means as discribed in GLOSSARY OF TERMS USED IN PHYSICAL ORGANIC CHEMISTRY (IUPAC Recommendations 1994) univalent group containing carbon, which is thus organic, but which has its free valence at an atom other than carbon. If the free valence bearing atom is an oxygen atom than the organohetryl group is referred to as "organyloxy". Likewise,"organylthio"and"organylaza"refer to organohetryl groups having a free valence bearing sulfur and nitrogen atom, respectively.

The term"organylene group"means a bivalent group conceptually derived by extracting a carbon hydrogen from an organyl group (see above). As any carbon atom may have the second free valence, organylene groups include methylene (and substituted derivatives), hydrocarbylene and so on.

The term"organohetryl-organyl group"means an organyl group (see above) having a second free valence at an atom other than carbon, i. e. an additional hydrogen is withdrawn from an occurring heteroatom. As such, these bivalent groups have a free valence both at a carbon atom and at an heteroatom.

The term"organohetryiene group"means an organohetryl group (see above) having a second free valence at an atom other than carbon, i. e. an additional hydrogen is withdrawn from a heteroatom.

The present invention provides novel nonporphyrin compounds comprising the structure of Formula 1 as defined herein useful for biochemical, biomedical and medical applications and applications as described hereinafter. The compounds of the present invention, when appropriately labeled, enable imaging and imaging related applications.

When labeled by chelation with radioactive and/or non radioactive, optionally paramagnetic, metal ions contrast agents are formed for imaging and imaging aided applications, such as for example MRI, NS, MRI aided applications and NS aided applications. In particular are mentioned in vivo imaging and in vivo imaging aided applications. These comprise the use of the novel by chelation labeled compounds as contrast agents, including multipurpose and disease specific contrast agents, for visualising and/or identifying diseases, pathologies, organs, parts of organs, systems such as for example the vasculatory, the hepatobiliary and the renal-urinary system, tissues such as for example necrotic tissue and the fluid tissue blood. The novel by chelation labeled compounds are particularly useful for medical applications in conditions involving necrosis and necrosis related pathologies, such as for example pathological and therapeutic necrosis caused by ischemia or originating from trauma, radiation and or chemicals.

In the compounds according formula 1, a direct link or a linking agent L covalently links a ring system A with a ring system B.

In ring system A, Z1 preferably represents the atoms necessary to complete a substituted or unsubstituted unsaturated or partially saturated monocyclic or polycyclic carbocyclic or heterocyclic ring system around an S1 substituted nitrogen atom. Whereas carbocyclic herein means that the ring system comprises no other hetero atoms than the S1 substituted nitrogen atom, heterocyclic refers herein to ring systems which comprise in addition to the S1 substituted nitrogen atom one or more additional hetero atoms (e. g. N, 0 and S) or combinations thereof. As used herein monocyclic refers to a 3-, 5-or 6-membered ring skeleton. As used herein, polycyclic refers to ring skeletons containing two or more fused component rings, said adjoining component rings share 2 or more atoms and component rings have a 3-, 4-, 5-, 6-or 7-membered ring skeleton. Suitable monocyclic ring A systems comprise for example : pyrrole, pyrroline, pyrrolidine, imidazol triazole, piperazine, tetrahydropyridine and morpholine. Suitable polycyclic ring A systems comprise for example bicyclic and tricyclic rings. Exemplary bicyclic rings include tetrahydroisoquinoline, indazole, indole, indoline, benzotriazol, decahydroquinoline and purine. Examplary tricyclic rings include azepine, hexahydroazepine, iminodibenzyl, phenoxazine, phenothiazine, dihydroacridine and carbazole. Preferred ring systems A are pyrrole and indole.

In ring system B, Z2 preferably represents the atoms necessary to complete a substituted or unsubstituted unsaturated, partially saturated or aromatic monocyclic or polycyclic carbocyclic or heterocyclic ring system around an S2 substituted X atom, wherein X represents carbon or an S2 substituted nitrogen atom.

If X is an S2 substituted nitrogen atom, then the description of ring system B is identical with that of ring system A.

If X stands for carbon then carbocyclic herein means that the ring system comprises no hetero atom, heterocylcic herein refers to ring systems which comprise one or more additional hetero atoms (such as N, 0 and S) or combinations thereof. As used herein monocyclic refers to a 3-, 5or 6-membered ring skeleton. As used herein, polycyclic refers to ring skeletons containing two or more fused component rings, said adjoining component rings share 2 or more atoms and component rings have a 3,4, 5,6 or 7 membered ring skeleton.

Suitable monocyclic ring B systems (with X standing for carbon) comprise for example : benzene, pyridine, furan, thiophene, pyrimidine and pyrazine. Suitable polycyclic ring B systems (with X standing for carbon) comprise for example bicyclic and tricyclic rings. Exemplary bicyclic rings include naphtalene, quinoline, quinoxaline, benzothiazole, benzofuran, dihydrobenzofuran.

Examplary tricyclic rings include phenanthroline and anthracene. Preferred ring systems B (with X standing for carbon) are benzene and naphthalene.

Among the compounds comprising a ring system B wherein X stands for carbon, preferred, but nonlimiting, are compounds comprising a ring B system according to the following partial formula 4,

wherein - L, C2, C3, R2 are as in the above formula 1; - Z3 represents the atoms necessary to complete a substituted or unsubstituted unsaturated, partially saturated or aromatic monocyclic or polycyclic carbocyclic or heterocyclic ring system fused with a benzene ring that is involved in the link with ring system A and bears a substituent YH; - the benzene substituent YH refers to functional groups such as for example hydroxy (-OH), thiol (-SH) and amino (-NH2). Preferred ring B systems comprising formula 4 are phenol, aniline, naphthol and tetrahydronaphthol, In the compounds comprising formula 1, the amino subtituents S1 and S2 stand independently for hydrogen or for a functional group, for a saturated or partially unsaturated alkyl, aryl or aralkyl chain optionally comprising one or more heteroatoms or combinations thereof and optionally bearing one or more functional groups, said the S substituent (S1 and S2) if not hydrogen or a functional group (such as for example formyl) is bonded to the nitrogen of the ring system (=N-S) via a direct bond (=N-CH2-x), as carbamate (=N-C (O)-O-x and =N-O-C (O)-N (-y) -x), as amide (=N-C (O)-x), as ureide (=N-C (O)-N (-y) -x), as phosphinamide (=N-P (O) (-y) -x), as phosphoramidate (=N-P (O) (O-y)-O-x), as sulfenamide (=N-S-x), sulfonamide (=N-S02-x), or as silyl (=N-Si (-z) (-y)-x) wherein x, y and z are the residues necessary to complete the S subtituent. Prefered S subtituents comprise hydrogen, formyl or C1 to C20 straight chain or branched chain alkyl, aryl or aralkyl groups optionally comprising one or more heteroatoms or combinations thereof such as N, 0, S, Si and optionally bearing one or more functional groups such as for example nitro, hydroxy, mercapto, imino, oxo, thioxo, sulfo, amino and/or carboxy group (s). Also prefered are groups involving bonds which can be cleaved either in vitro or in vivo. Of particular use are amino protective groups, well-known from the general synthetic literature and from the vast amount of literature dealing with pyrrole and indole chemistry.

In the compounds comprising formula 1, hydrogen atoms on carbon atoms constituting the ring skeletons (ring system A and ring system B) may be partially replaced by halogen atoms such as iodo, chloro, bromo and/or fluoro.

In the compounds comprising formula 1, ring system A and ring system B are joined together either by a direct link or via a linking agent. Direct bonding may join any carbon or any optional hetero atom other than the S1 substituted N atom from the ring system A with any carbon or any optional hetero atom other than the optional S2 substituted N from the ring system B (if a ring system B is selected according to formula 4 than a benzene carbon atom is selected). Prefered direct bonds are C-C, C-N and N-N bonds.

If L means a linking agent Li, than Li represents: - a straight chain or branched-chain, saturated, partly saturated or partly aromatic group, designated as organylene, organohetryl-organyl or organohetrylene ; - a bridging heteroatom such as for example oxygen (a-O-w) or sulfur (a-S-w) - a bridging functional group not comprising carbon, such as for example aminyl (a-NH-M and Rxn N-substituted derivatives a-N (Rxn)-w), hydrazo (a-NH-NH-co, as well as Rxh N-substituted and Rxh, Ryh N, N'-substituted derivatives), sulphonohydrazide (a-S (=0) 2--NH-NH-o), suiphonamide (a-S (=0) 2-NH-M), sulphonyl (a-S (=0) 2-#) ; - a bridging functional group comprising carbon, such as for example acyl (a-C (=O)-o, a-C (=N-Rxn)- m), ester (a-C (=O)-O-#), imine (including aldimine a-N=CH-o) and ketimine a-N=C (Rxk)- w), urethane (a-N (Rxu)-C (=O)-O-#), hydrazide and Rxh N-or N'-substituted and Rxh, Ryh N, N'-substituted hydrazides comprising carbonhydrazide (a-C (=O)-NH-NH-m and derivatives), sulphonohydrazide (a-S (=0) 2-NH-NH-# and derivatives) aswel as their acyl derivatives (such as for example α-C(=O)-NH-NH-C(=O)-#), amide including primary amide (a-C (=O)-NH-M and N-substituted a-C (=O)-N (Rxd)- 00 derivatives) and secondary amide (a-C (=0)-NH-C (=0)-M and a-C (=O)-N (-C (=O)-Rxa)-o)), sulphonamide (a-S (=0) 2-NH-M and Nsubstituted derivatives a-S (=0) 2-N (Rxs)-M) wherein Rx and Ry type substituents are as desribed below. As used herein and hereinbelow, arefers to the free valence by which the linking agent is connected to either ring system A or ring system B of formula 1 so that-M (or M-) mutually exclusively stands for the valence connecting the linking agent with the other ring system (ring system B and ring system A, respectively).

Suitable bridging groups can be selected from: the category having a bridging bivalent carbon atom and derivatives thereof, such as methylene (a-CH2-M), substituted methylene (a-CH (R3a)-M and a-C (R3b) (R3a)-o) including -ylidene substituted methylene (α-C[=C(Ryi)-Rxi]-#), acyl (a-C (=O)-o)) ; the category comprising optionally R3 and/or C3 substituted bridging straight chain or branchedchain, saturated, partly saturated or unsaturated hydrocarbylene or derived hydrocarbylene groups, which optionally comprise: - one or more hetero atoms such as oxygen (-0-) and/or sulfur (-S-) ; - one or more functional chain elements, selected from the list comprising acyl (-C (=O)-, - C (=S) -, -S (=0) 2-,-C 2-, -C(=N-Rxn)-,-P (=O) (-Rxp) -), ester (-C (=O)-O-,-C (=O)-S-,

-C (=S)-O-,-S (=0) 2-0-, O-O-P (=O) (OH)-O-), aminyl (-NH-and N-substituted derivatives - N (Rxn) -), imine (including aldimine-N=CH-and ketimine-N=C (Rxk) -), urethane (-N (Rxu)-C (=O)-O-), hydrazo (-NH-NH-as well as Rxh N-substituted and Rxh, Ryh N, N'substituted derivatives), hydrazide and Rxh N-substituted and Rxh, Ryh N, N'-substituted hydrazide comprising carbonhydrazide (-C (=O)-NH-NH-), sulphonohydrazide (-S (=0) 2-NH-NH-) aswel as their acyl derivatives (such as for example -C (=O)-NH-NH-C (=O)-), amide including primary amide (-C (=O)-NH- and N-substituted -C (=O)-N (Rxd)- derivatives) and secondary amide (-C (=O)-NH-C (=O)- and -C (=O)-N (-C (=O)-Rxa)-), sulphonamide (-S (=0) 2-NH- and N-substituted derivatives -S (=0) 2-N (Rxs)-) wherein Rx and Ry type substituents are as desribed below ; one or more saturated, partly unsaturated and/or aromatic optionally substituted carbocyclic and/or heterocyclic rings, which optionally comprise one or more of the above mentioned functional chain elements.

As used herein, derived hydrocarbylene group include - organylene groups in which the free valence a-and/or m-are optionally located on an acyl carbon (α/#-C (=O)-) and/or a functional chain element comprising such an acyl carbon (such as for example α/#-C(=O)-NH-NH- as well as Rxh N or N'-substituted and Rxh, Ryh N, N' substituted derivatives, a/m-C (=O)-O-, α/#-C(=O)-NH- and N-substituted derivatives ww-C (=O)-N (Rxd) -), - organohetryl-organyl groups in which an oxygen (organyloxy), a nitrogen (organylaza) or a sulfur atom (organylthio) bears a free valence (a-), the remaing free valence #- being localized on a carbon atom (including an acyl carbon), - and organohetrylene groups in which both the free valence a-and m-are localized on an hetero atom, freely selected as oxygen (organyloxy), nitrogen (organylaza) or sulfur (organylthio), Suitable organyloxy chain ends may be selected from the list comprising end standing ether (α/#-O-) and ester functions (a/M-O-C (=O)-, a/m-O-C (=S) -, α/#-O-S(=O)-).

Suitable organylaza chain ends may be selected from the list of end standing functional groups comprising aminyl (a/M-NH-and N-substituted derivatives α/#-N (Rxn) -), imine (including aldimine a/m-N=CH-and ketimine α/#-N=C (Rxk) -), urethane (α/#-N (Rxu) -C (=O)-O-), hydrazo (a/M-NH-NH-as well as Rxh N-or N'-substituted and Rxh, Ryh N, N'-substituted derivatives), hydrazide and Rxh N-or N'-substituted and Rxh, Ryh N, N'-substituted hydrazide comprising carbonhydrazide (α/#-NH-NH-C(=O)- and derivatives) and sulphonohydrazide (a/M-NH-NH-S (=0) 2- and derivatives), amide (a/M-NH-C (=O)-), sulphonamide (o/m-NH-S (=0) 2-).

Suitable organylthio chain ends may be selected from the list of end standing functional groups comprising thioether (α/#-S-), thioester functions (a/m-S-C (=O)-) and sulphonamide (a/M-S (=0) 2-NH-).

Exemplary methylene type bridges comprise, methylene as such (a-CH2-o), substituted methylene bridges (a-CH (R3a)-co and a-C (R3b) (R3a)-m) according to the following formula 5 and - yiidene substituted methylene (a-C [=C (Ryi)-Rxi]-M) according to the following formula 6.

In formula 5 the linking agent is methylene or substituted methylene,

whereby R3a and R3b are both hydrogen,, C3 is an optional C-function attached via an R3a substituent ; R3b and R3a are substituents formally derived from an aldehyde of formula H-C (=O)-R3a or a ketone of formula R3b-C (=O)-R3a wherein the carbonyl function gives rise to the a-C-Oo methylene bridge carbon atom.

Accordingly, linking agents represtented by substituted methylene may be formally derived from aliphatic and aromatic aldehydes and aliphatic and aromatic ketones. Aromatic formyl compounds being particularly preferred. A selection of suitable examples of the latter comprise : benzaldehyde, 2-mercaptobenzaldehyde, 4-mercaptobenzaidehyde, 3-benzyloxybenzaldehyde, 4biphenylcarboxaldehyde, 2-bromobenzaldehyde, 3-bromobenzaldehyde, 4-bromobenzaldehyde, 3chlorobenzaldehyde, 4-chloro-3-nitrobenzaldehyde, 4-cyanobenzaldehyde, 2, 6dichlorobenzaldehyde, 4- (diethylamino) benzaldehyde, 2, 5-dihydroxybenzaldehyde, 3, 4dihydroxybenzaldehyde, 2, 3-dimethoxybenzaldehyde, 2, 4-dimethoxybenzaidehyde, 2, 5dimethoxybenzaldehyde, 2, 4-dinitrobenzaldehyde, 4-ethoxy-3-methoxybenzaldehyde, 2fluorobenzaldehyde, 3-fluorobenzaldehyde, 5-formylsalicylic acid, 3-hydroxybenzaldehyde, 2nitrobenzaldehyde, 3-nitrobenzaidehyde, salicylaldehyde, 3, 5-dimethoxy-4-hydroxybenzaldehyde, m-tolualdehyde, p-tolualdehyde, 3, 4, 5-trimethoxybenzaldehyde, pentafluorobenzaldehyde, 4dimethylaminobenzaldehyde, 4-chlorobenzaldehyde, 2-carboxybenzaldehyde, o-tolualdehyde, 3, 5dibromosalicylaldehyde, 4-benzyloxybenzaldehyde, 4-carboxybenzaldehyde, 2chlorobenzaldehyde, 3, 5-dimethoxybenzaldehyde, 3-ethoxy-4-hydroxybenzaldehyde, 4fluorobenzaldehyde, 4-nitrobenzaldehyde, 2, 4, 5-trimethoxybenzaldehyde, 5-bromosalicylaldehyde, 2, 4, 6-trimethoxybenzaldehyde, 2-chloro-5-nitrobenzaldehyde, 3, S-dichlorobenzaldehyde, 3, 5-di

tert-butyl-4-hydroxybenzaldehyde, 2-chloro-6-fluorobenzaldehyde, 3-hydroxy-4methoxybenzaldehyde, 3, 4-dimethoxybenzaldehyde, 4-hydroxybenzaldehyde, 4-hydroxy-3nitrobenzaldehyde, 3-cyanobenzaldehyde, 2, 4-dichlorobenzaldehyde, 2-hydroxy-5methoxybenzaldehyde, 2-fluorenecarboxaldehyde, 2, 4-dimethylbenzaldehyde, 2, 5dimethylbenzaldehyde, 2-methoxy-l-naphthaldehyde, N-ethyl-3-carbazolecarboxaldehyde, 2, 5dimethyl-p-anisaldehyde, 2, 3, 4-trimethoxybenzaldehyde, 3-methyl-p-anisaldehyde, 2formylphenoxyacetic acid, 2-ethoxybenzaldehyde, 5-bromo-2-anisaldehyde, 6bromoveratraldehyde, 2-hydroxy-4-methoxybenzaldehyde, 4-benzyloxy-3-methoxybenzaidehyde, 3-benzyloxy-4-methoxybenzaldehyde, 2, 4-dihydroxybenzaldehyde, 4-ethoxybenzaldehyde, 4formylcinnamic acid, 2, 3-dihydroxybenzaldehyde, 3-phenoxybenzaldehyde, 3- (4chlorophenoxy) benzaldehyde, 3- [3- (trifluoromethyl) phenoxy] benzaldehyde, 3- (4methoxyphenoxy) benzaldehyde, Alpha, Alpha, Alpha-trifluoro-m-tolualdehyde, 4phenoxybenzaldehyde, 4- (methylthio) benzaldehyde, Alpha, Alpha, Alpha-Trifluoro-p-tolualdehyde, 4- (diethylamino) salicylaldehyde, 4-butoxybenzaldehyde, 2-formylbenzenesulfonic acid sodium salt, methyl 4-formylbenzoate, 2, 3-dichlorobenzaldehyde, 2, 3, 6-trichlorobenzaldehyde, 2, 3, 5trichlorobenzaldehyde, 2, 6-diformyl-4-chlorophenol, 2, 6-diformyl-4-methylphenol, 3, 4difluorobenzaldehyde, 3-formylsalicylic acid, 4-bromo-2-fluorobenzaldehyde, 4-chloro-2fl uorobenzaldehyde, 3-bromo-4-methoxybenzaldehyde, 4-octyloxybenzaldehyde, 3', 4' (dioctyloxy) benzaldehyde, 4-decyloxybenzaldehyde, 3', 4'- (didecyloxy) benzaldehyde, 4dodecyloxybenzaldehyde, 3', 4'- (didodecyloxy) benzaldehyde, 3, 5-difluorobenzaldehyde, 4 (trif) uoromethoxy) benza) dehyde, 3-bromo-4-ftuorobenza) dehyde, 5-bromo-2-f) uorobenza) dehyde, 4-chloro-3-fluorobenzaldehyde, 3, 4-dichlorobenzaldehyde, terephthaldehyde monodiethylacetal, 3carboxybenzaldehyde, 3- (trifluoromethoxy) benzaldehyde, 2-chloro-4-fluorobenzaldehyde, 2, 3difluorobenzaldehyde, 2, 5-difluorobenzaidehyde, 2, 6-dimethoxybenzaldehyde, 3, 5bis (trifluoromethyl) benzaldehyde, 3-chloro-4-fluorobenzaldehyde, 2, 6-difluorobenzaldehyde, 4fluoro-2- (trifluoromethyl) benzaldehyde, 4-ethylbenzaldehyde, 5-chloro-2-nitrobenzaldehyde, 2ethoxy-1-naphtaldehyde, 2-amino-3, 5-dibromobenzaldehyde, 4-isopropylbenzaldehyde, pentamethylbenzaldehyde, 4-hydroxy-2-methoxybenzaldehyde, p-acetaminobenzaldehyde, 2, 4, 5trihydroxybenza) dehyde, 5-bromo-2-hydroxy-3-methoxybenza) dehyde, 2, 3-dibromo-4-hydroxy-5methoxybenzaldehyde, 4-benzyloxy-3, 5-dimethylbenzaldehyde, 3, 4-dimethylbenzaldehyde, 2, 4, 6trihydroxybenzaldehyde, 4-acetamidobenzaldehyde, 5-chlorosalicylaldehyde, 3, 5dichlorosalicylaldehyde, 4-formylphenoxyacetic acid, 4-hexyloxybenzaldehyde, 4methoxybenzaldehyde-3-sulfonic acid sodium salt, 3-nitrosalicylaldehyde, 2-hydroxy-5nitrobenzaldehyde, 4-octylbenzaldehyde, 2, 3, 4-trihydroxybenzaldehyde, 4-methylsulphonyl

benzaldehyde, 2-Hydroxy-1-naphthaldehyde, 1-naphthaldehyde, 2-naphthaldehyde, 4-methoxy-1naphthaldehyde, 9-anthracenecarboxaldehyde, 10-methylanthracene-9-carboxaldehyde.

In formula 6 the linking agent is a carbon atom with an-ylidene substituent

wherein Rxi and Ryi are equal or different and stand for hydrogen, an R3c substituent, a C3 substituent or Rxi and Ryi together with the-ylidene C-atom may form a 5 or a 6-membered ring that is optionally substituted with R3 or C3. Examples of suitable cyclic-ylidene substituents are:

3-carboxy-4-oxo-2, 5-cyclohexadien-1-ylidene, 3-carboxy-4-oxo-5-methyl-2, 5-cyclohexadien-1-ylidene, 3-sulfo-4-imino-2, 5-cyclohexadien-1-ylidene

Exemplary carbocyclic chain components include bivalent rings such as cyclohexylene, phenylene, phenyleneoxy, phenylenedioxy, phenyleneimino, phenylenedimino.

Exemplary heterocyclic chain components include bivalent rings such as 2, 5-thiophenylene, 2, 5-pyrrolylene, N, N'-piperazine, N, N'azacyclic compounds such as N, N'cyclen (1, 4,7, 10 tetraazacyclodocecane), N, N' pentacyclen (1,4, 7,10, 13-pentaazacyclopentadecane) and N, N hexacyclen (1,4, 7,10, 13, 16-hexaazacyclooctadecane).

Exemplary hydrocarbylene and derived (e. g. N-substituted) hydrocarbylene chains or chain components, may be further selected from the group of, optionally further derived (by Rx and/or Ry), bivalent moieties consisting essentially of: - (CH2) n- (n=1-10) and (poly) hydroxy derivatives, - CH2-0- (CH2) 2-0-CH2-, - (CH2-0-CH2) n- (n=1-3), -CH2-S-CH2 -CO-NH-NH-, - CO-NH-N (CH2CHOH) -.

-CO-NH-N (CH2COOH)-, -CO-NH-N(-(CH2) n-CH3) - (n=0, 1), - CO-NH-N (-CeH5)-, -CO-N(-C6H5)-N(-C6H5)-, - CO-NH-N (-CH2-CeH5)-, -CHOHCH2-O-CH2CHOH-,

- CO-N (-CH2-CeH5)-N (-CH2-C6H5)-, - CHOHCH2-0- (CH2) n-O-CH2CHOH- (n=4), - (CH2) 2-S02- (CH2) 2-, -(CH2CH2-O)n-(CH2) 2- (n=4), -NHCO-(CH2) n-CONH- (n= 1-x), -N(-(CH2) n-CH3) -N (- (CH2) n-CH3) - (n=0, 1),

- N (CH3) CO- (CH2) n-N (CH3) CO- (n= 1-2), - N (CH3) CO-CH2-O-CH2-N (CH3) CO-, - NHCO- (CH2) n-NHCO- (n= 1, 2, 4), - CONH- (CH2) n-NHCO- (n= 2), -NH-NH-CO-(CH2)n-CO-NH-NH - CON (CH3) -N (CH3) CO - CONH-NHCO-, -CONH-CH (CO2H)- (CH2) n-NHCO- (n= 5), -CONH-(CnH2n-O)-m-CnH2m-NHCO- (n= 2 or3, m=1-5), -CON(CH3)--(CnH2n-O)m-CnH2m-H(CH3)-CO- (n= 2 or3, m=1-5),

-CONH-CH2- (CH2CH2-O) n- (CH2) 3-NHCO- (n= 4), - CON (CH3)- (CH2CH2-0) n- (CH2) 2-N (CH3) CO- (n= 2, 3, 5), -CON (CH3)-CH2- (CH2CH2-O) n- (CH2) 3-N (CH3) CO- (n= 4), -(CH2)2-NH- , -(CH2)2-O-C6H4-CH2- , -(CH2)3-O-C6H4-CH2- , -CH2-CHOH-CH2-O-C6H4-CH2-, -C(=NH)-O-C6H4-CH2- , -(CH2)4-NH-CO-CH2-C6H4-CH2- , -(CH2)4-NH-CO-(CH2)8- , -(CH2)4-NH-CH2-CHOH-CH2-C6H4-CH2- , -CH2-CO-NH-(CH2)3-O-CH2- , -CH2-CO-NH-NH-, -CH2-CO-NH- (CH2) 2 -CH2-CO-NH-(CH2)10-, -CH2-CO-NH- (CH2) 2-S

-CH2-CO-NH- (CH2) 3-NH - (CH2) a-NH-, - CH2-NH-C (=S)-NH-C6H4-CH2-, - (CH2) 2-NH-CO-CH2- (CH2CH2-O) n-0-CH2- (n=3, 4), -CH2-NH-C(=O)-NH-CH2- , -CO-NH-,

- CH2- (N (-CH2-) nN) CH2- (piperazine n=4, homopiperazine n=5), - (N (-CH2-) nN) CH2- (piperazine n=4, homopiperazine n=5), - (N (-CH2-) nN)- (piperazine n=4, homopiperazine n=5), -CH2-, -C(C6H5)(OH)-, -CH (C6H5)-, -CHOH-, -(C2N2O)- (oxadiazole), -NH-C (=O)-NH -(C6H5)-NH-C(=O)-NH-(C6H5) -(C5H3N) - (CsH2N) (-CH3) - HC=N- (C6H1o)-N=CH -H2C-NH-(C6H10)-NH-CH2- -C (=O)-C (=O) -O-C(=O)-C(=O)-O- -C=(C6H2)(=O)(-CH3) =C -CH2-O-C(=O)-(CH2) n-C (=O)-O-CH2- (with n = 2-10) - S-, -SO2-, - S02-NH- (C6H5)-, -SO2-NH -CO-, -SO2-NH-NH-, - NH-NH-, - NH-N (CH2CHOH) -, - NH-N (CH2COOH) -, -NH-N(-(CH2)n-CH3)- (n=0, 1), -NH-N (-C6H5)-, -N (-C6H5)-N (-C6H5)-, -NH-N (-CH2-C6H5)-, -N (-CH2-C6H5)-N (-CH2-C6H5)-, In the above and further herewithin Rx and Ry type substituents, optionally further specified by an aditional index (h, n, d, s, u, a, i, m, k, p) and a number (1,2) refer to substituents or exceptionally to parts of substituents of - the nitrogen atom as occurring in hydrazide and the hydrazo group (Rxh and Ryh), as present in aminyl (Rxn and Ryn), in amide (Rxd) in sulfonamide (Rxs) and urethane (Rxu); - the phosphor atom as part of an acylmoiety such as-P (=O) (-Rxp) - - the carbon atom as occuring in ketimine (Rxk), - the carbon as chain part of an N acylsubstituent in bis acyl amide such as-C (=O)-Rxin ; the carbon atom as occuring in-ylidene substituted methylene (a-C [=C (Ryi)-Rxi]-o)) ; Rx and Ry represent 1, l' or l" as will be defined hereinbelow.

In compounds according to formula 1, said compounds according to the above description comprising a ring system A and a ring system B that are joined together by either a direct link or by a linking agent, R and C refer to partly optional substituents of ring system A (R1, C1), substituents of ring system B (R2, C2) and substituents of the linking agent (R3, C3). If labeling is accomplished by metal chelation the compound should comprise at least one substituent referred to as C (C1, C2 or C3). Prefered C-functions are organyl and organohetryl groups of the general formula 7: ss- (K-8) o-1-CA formula 7 in which a cheating agent CA is either directly ( (3-CA) or via a bivalent chain (3-K-8 connected as C-function as in general formula 1; ss indicates the bond to the joined ring system A and ring system B as in general formula 1, 8 indicates the bond of K to molecule portion CA. The bivalent chain P-K-8 may stand for a bridging agent selected from the linking agents (a-Li-M), which have been described above, whereby K stands for Li and the bond ss represents either a or on, so that bond mutually exclusively stands for m and a, respectively. The molecule portion CA is here desribed as an organyl or an organohetryl group comprising in its substructure: - one or more thiol bearing moieties such as for example bisamine-bisthiol, bisamine-bisoxime, monomercapto-triamide, diamide-dithiol, monoamine-monoamide-dithiol, tetramine, monoaminediamide-monothiol, monoamine-monothioether-dithiol, monoamine-monothiol, monoamidediamine-monothiol and diphosphine based moieties; and/or - one or more structural elements with the following structural formulas 8 and 9:

wherein Z'stands for a radical selected from the list comprising: phosphonomethyl (-CH2PO3HRz), carboxy methyl (-CH2COORz) and its derivatives (-C (Zx) HCOORz), carboxy ethyl (-CH2CH2COORz) and its derivatives (-C (Zx) HCH2COORz and-CH2C (Zy) HCOORz), and wherein Z'stands for hydrogen or a radical selected from the list comprising: phosphonomethyl (-CH2PO3Rz), carboxy methyl (-CH2COORz) and its derivatives (-C (Zx) HCOORz), carboxy ethyl (-CH2CH2COORz) and its derivatives (-C (Zx) HCH2COORz and-CH2C (Zy) HCOORz), hydroxyethyl (-CH2CH2ORz) and its derivatives (-C (Zx) HCH20Rz and-CH2C (Zy) HOH); whereby N-atom together with Z'and the optional Z"stand for example for iminoacetic acid (- (-) N-CH2COORz), iminopropionic acid (- (N-CHsCHsCOORz)), iminodiacetic acid (-N (CH2COORz) 2), iminodipropionic acid (-N (CH2CH2COORz) 2), iminoacetic propionic acid (-N (CH2CH2COOH) (CH2COOH)), hydroxyethyl iminoacetic acid (-N (CH2COORz) (CH2CH20H)) and hydroxyethyl iminopropionic acid (-N (CH2CH2COORz) (CH2CH20H)) group (s); in the cited examples Zx, Zy and Rz are in the meaning as desribed hereinbelow.

Preferred CA-moieties are organyl or organohetryl groups comprising in their structure formula 10 or formula 11

wherein - the index a of formula 11 stands for the numerals 0 to 6 - at least one carbon or one hetero atom is involved in covalent ss or 8 bonding at the hereinbelow cited locations; - each V may stand independently of one another, for an, optionally substitute, saturated, partly unsaturated, aromatic or partly aromatic organylene group, said V may stand for optionally substituted phenylen, optionally substituted diphenylen and for an optionally substituted C2 C30 straight-chain or branched-chain hydrocarbylene group wherein the chain or parts of the chain can form a cyclic C5-C8 unit or a bicyclic C10-C14 unit; the hydrocarbylene group may also contain phenylene (-C6H4-), oxygen (-0-), sulfur (-S-), aminyl (-NH-), N-substituted aminyl - NRxn-and-N (-Z) -), aminyl as part of the aforementioned cyclic units (-N (-)-), aminyl involved in ss or 8 bonding carbonyl (-C (=O)-), thiocarbonyl (-C (=S) -) ; the hydrocarbylene group may be optionally substituted by halogens and/or functional groups (such as for example epoxy, hydroxy, alkoxy, nitro, aminyl, sulpho, thiol, and the like) and/or by lower (hetero) alkyl, (hetero) aryl and/or (hetero) aralkyl groups that are optionally substituted by halogens and/or by functional groups; additional optional hydrocarbylene substituents include the, optionally by halogens and/or by functional groups substituted, radicals

- (CH2) 0-5- (C6H4) 0-1- (O) o.,- (CH2) 0-5- (C6H4) 0-1- (0) 0-1-M and - (CH2) o-5- (C6H10) o-r (0) o-i- (CH2) o-s- (C6H4) o. i- (0) o. i-M wherein the molecule portion M stands for hydrogen, Rz, Q or a-CH2CH2-Q group with Q, Z and Rz as described hereinbelow ; each aminyl Z-substituent may stand independently of one another for hydrogen, for the organyl groups -CH(Zx)-[-(CH(Zy)-]0-1-Q, -C(=O)-CH (Zx) -Q wherein the molecule portion Q stands for a direct bond (ss or 8) or a bonding group comprising - C (=0)-p/8 or-NH-p/8, phosphono (-P03H2) or derivatives thereof (-P03HRz), carboxy (-COOH) or derivatives thereof (-COORz), amide (-C (=O)-NH2) or derivatives thereof (-C (=0)-NH-Rzd1 and-C (=O)-N (-Rzd2)-Rzd1), hydrazide (-C (=0)-NH-NH-Rzh1 and - C (=0)-NH-N (-Rzh2)-Rzh1), hydroxy (-OH) and derivatives (-ORz), thiol (-SH) and derivatives (-SRz), a small saturated, partly saturated or aromatic 5 or 6 membered heterocyclic organyl or organohetryl group comprising one or more heteroatoms and optionally substituted by 1 to 3 substituents independently selected from the list comprising functional groups and/or lower alkyl groups; wherein Zx and Zy are selected from the list essentially comprising a direct bond (ss or #) or a bonding group comprising-C (=O)- and/or -NH- involved in p or 8 bonding, hydrogen, carboxy (-COORz), a straight or branched 2-alkenylgroup or derivatives thereof involved in ss or 8 bonding, the lower alkyl, aryl and aralkyl group optionally substituted by halogens and/or functional groups (such as hydroxy, alkoxy, carboxy, epoxy, nitro, amino, and the like) and optionally comprising one or more heteroatom (s), the, optionally by halogens and/or by functional groups substituted, radicals

- (CH2) o-5- (C6H4) o-1- (O) o-i- (CH2) o. 5- (C6H4) o. i- (O) o-1-M and - (CH2) o-5- (C6H10) o-1- (O) o. i- (CH2) o-5- (C6H4) o-1- (0) o-1-M ; wherein the molecule portion M stands for hydrogen, Rz, a-CH2CH2COORz group, a direct ss or 8-bond or a bonding group comprising-C (=O)- and/or-NH-involved in ss or 8 bonding, a small saturated, partly saturated or aromatic 5 or 6 membered heterocyclic organyl or organohetryl group comprising one or more heteroatoms and optionally substituted by 1-3 substituents independently selected from the list comprising functional groups and/or lower alkyl groups; with the radicals Rzh1, Rzh2, Rzd1, Rzd2 and Rz as described hereinbelow.

In the above description and hereinbelow, Rzh1 and Rzh2 stand for substituents of the N'-nitrogen occuring in hydrazide, include hydrogen; Rzd1 and Rzd2 stand for substituents of the nitrogen occuring in amide, include hydrogen In the aforementioned description and hereinbelow, each Rz may be independently selected from the list comprising: hydrogen, organyl radicals such as for example optionally by halogens and/or functional groups substituted, straight chain or branched chain saturated or party unsaturated alkyl-, aralkyl-or aryl-groups, bonds involved in metal complexation. Moreover, Rz is also used in the meaning of an organic or inorganic cation replacing an acidic Rz-proton.

Preferred Rz organyl radicals are for example C1-C20 branched chain or straight chain alkylgroups which are optionally substituted with halogens and/or functional groups, aryl-, arylmethyl-, bisarylmethyl-, trisarylmethyl-and arylethyl-radicals in which the aryl is optionally substituted with 1 to 3 groups independently selected from halogens, functional groups (such as for example nitro, carboxy, amino, aminyl, amide, sulphono, hydroxy, ), C1-C15 alkyl, C1-C15 substituted (halogens and/or functional groups) alkyl, C1-C15 acyl, C1-C15 substituted (halogens and/or functional groups) acyl, alkoxy, arylalkoxy ; accordingly suitable examples of Rz organyl radicals include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, tert-pentyl, hexyl, 2-ethylhexyl, heptyl, octyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, 2-hydroxyethyl, pyridyl, phenyl, nitrophenyl, naphthyl, di-tertpentylphenyl, diphenylmethyl, bis (4-fluorophenyl) methyl, diethylaminobenzyl, bis (trifluoromethyl) benzyl, benzyloxymethyl, triphenylmethyl. However, Rz is not limited to these examples In the aforementioned aminyl Z-substituents, examplary substituents Zx and Zy include but are not restricted to hydrogen, 2-alkenylgroup having 2-6 carbon atoms such as for example allyl, 2-butenyl, 2-pentenyl, 2-hexenyl group and derivatives thereof involved in ss or 8 bonding, carboxy (-COOH), benzyl, benzyl substituted by functional groups (such as hydroxy, carboxy, sulphono, nitro, amino, alkoxy and the like) according examples comprise-CH2-C6H5,-CH2-C6H4-OH, -CH2-C6H4-OCH3,-CH2-C6H4-OCH2CH3,-CH2-C6H4-OCH2COORz,-CH2-C6H4-NH2, -CH2-C6H4-C (=O) NH2;-CH2-0-C6H5, organyl substituents comprising, optionally substituted,

partly saturated or aromatic 5 or 6 membered heterocycles include the non limiting examples (furfuryl) alkyl, (hydroxyfurfuryl) alkyl, (imidazolyl) alkyl, (imidazolyl) alkyl. However, Zx and Zy are not limited to these examples.

As molecule portion V in formula 10 and 11 can be mentioned by way of example : -CH2-CH2-,-CH2- (CH2) 3-12-, - (CH2) 2. 3-0- (CH2) 2-3-,- (CH2) 2-3-S- (CH2) 2-3-,-CH2-CH2- (0-CH2-CH2) 2-4 - CH2- (C6H10)-CH2-,-CH2- (C6H4)-CH2-,-CH2- (C6H4)-O-CH2-, - (C6H10)-,- (C5H8)-,- (CH2) 2-3-N (-CH2CH2-) (-CH2CH2-) N- (CH2) 2. 3 substituted ethylene such as-C (=O)-CH2- and -CH (-Xe) -CH2- whereby Xe stands for lower straight chain or branched alkyl or alkyloxy chain (C1-C7), hydroxyalkyl, polyhydroxyalkyl, lower alkoxy, pyridyl, pyridylalkyl, furfuryl, furfurylalkyl, phenyl, benzyl, benzyl substituted by 1 or 2 functional groups (such as for example hydroxy, alkoxy, nitro, amino, carboxy, sulphon)], - (CH2) 2. 3- [NH- (CH2) 2-3] i-3- and N-substituted derivatives thereof wherby one or more aminyl hydrogen (s) are optionally substituted by Z-group (s) and/or Rz-group (s) such as in the following nonlimiting examples- (CH2) 2-3- (N (-Z) -CH2-CH2) 1-3-, -(CH2)2-3-NH-CH2-CH2-[N(-Z)-(CH2)2-3]1-2-, - (CH2) 2-3- (N (-Rz)-CH2-CH2h'3-,- (CH2) 2'3-N (-Rz)-CH2-CH2-[N (-Z)- (CH2h. 3]1'2-, Among the CA-moieties of formula 10 which comprise one or more thiol functions (-SH) and/or

derivatives thereof (-SRz), V in the meaning of-CH2-CH2-,-C (=O)-CH2-,-(CH2) 2-NH-(CH2) 2-, - (CH2) 2-N (-Z)- (CH2) 2-, is preferred. In this case, preferred are CA-moieties having one or more, aminyl Z-substituents selected independently from oneanother from the group essentially consisting of: thioethyl (-CH2CH2SH) and derivatives thereof (-CH2CH2SRz, -C (Zx) HC (Zy) SRz, -C (=O) CH2SRz), thiomethyl (-CH2SH) and derivatives thereof (-CH2SRz). Remaining aminyl Z substituents are preferably selected from the list essentially comprising: hydrogen, phosphonomethyl (-CH2PO3HRz), carboxy methyl (-CH2COORz) and derivatives thereof (-C (Zx) HCOORz, carboxy ethyl (-CH2CH2COORz) and derivatives thereof (-C (Zx) HC (Zy) HCOORz), hydroxyethyl (-CH2CH20H) and derivatives thereof (-CH2CH2ORz, - C (Zx) HC (Zy) ORz), thioethyl (-CH2CH2SH) and derivatives thereof (-CH2CH2SRz, - C (Zx) HC (Zy) SRz,-C (=O) CH2SRz), thiomethyl (-CH2SH) and derivatives thereof (-CH2SRz).

Aditionally, one or more of the remaing aminyl Z substituents can represent a small saturated, partly saturated or aromatic 5 or 6 membered heterocyclic organyl or organohetryl group comprising one or more heteroatoms and optionally substituted by a functional group and/or by a lower alkyl, non limiting examples are furfuryl, hydroxyfurfuryl, imidazolyl, methylimidazolyl, and the like.

As examples examples of the CA-moieties of formula 10 which comprise one or more thiol functions (-SH) and/or derivatives thereof (-SRz) are cited the organyl or organohetryl derivatives of a mercaptoacetyl tripeptide such as mercaptoacetyl triglycine (MAG3), a propylene diamine dioxime tetraligand bearing one or more alkyl substituents such as hexamethyl propylene diamine dioxime (HMPAO), ethylene dicysteine, ethylene cysteine cysteamine, cysteinylglycine cysteine, bismercaptoacetyldiaminopropionic acid, bismercaptoacetyldiaminosuccinic acid, N- (mercaptoacetylaminoethyl)-cysteine, dimercaptosuccinic acid, dimercaptopropionic acid, cysteine, cysteamine, diphosphinopropionic acid; and derivatives of the aforementioned whereby one or two thiol (-SH) functions are protected by a suitable Rz-group Among the CA-moieties of formulae 10 and 11 which do not comprise a thiol function (-SH), CA-moieties having at least one V in the meaning of-CH2-CH2-,- (CH2) z-NH- (CH2) 2-, - (CH2) 2-N (-Z)- (CH2) 2-,- (C6H10)-,- (C5H8)-, and the index a of formula 11 in the meaning of 0 or 1, are preferred.

In this case, preferred are CA-moieties having two or more, preferably 3 to 5, aminyl Z-substituents selected independently from oneanother from the group essentially consisting of: carboxy methyl (-CH2COORz) and derivatives thereof (-C (Zx) HCOORz, carboxy ethyl (-CH2CH2COORz) and derivatives thereof (-C (Zx) HC (Zy) HCOORz).

Remaining aminyl Z substituents are preferably selected independently from oneanother from the list essentially comprising: hydrogen, phosphonomethyl (-CH2PO3HRz), carboxy methyl (-CH2COORz) and derivatives thereof (-C (Zx) HCOORz, carboxy ethyl (-CH2CH2COORz) and derivatives thereof (-C (Zx) HC (Zy) HCOORz), hydroxyethyl (-CH2CH20H) and derivatives thereof (-CH2CH2ORz,-C (Zx) HC (Zy) ORz). methylamide (-CH2C (=O)-NH2) or derivatives thereof (-CH2C (=O)-NH-Rzd1 and-CH2C (=O)-N (-Rzd2)-Rzd1), ethylamide (-CH2 CH2C (=O)-NH2) or derivatives thereof (-CH2CH2C (=O)-NH-Rzd1 and-CH2CH2C (=O)-N (-Rzd2)-Rzd1), methylhydrazides (-CH2C (=O)-NH-NH-Rzh1 and-CH2C (=O)-NH-N (-Rzh2)-Rzh1), ethylhydrazide (-CH2CH2C (=O)-NH-NH-Rzh1 and-CH2 CH2C (=O)-NH-N (-Rzh2)-Rzh1).

Aditionally, one or more of the remaining aminyl Z substituents can represent a small organyl substituent. As small organyl substituents can be cited: lower straight-chain or branched-chain saturated or partly unsaturated alkyl groups which are optionally substituted by halogens and/or by functional groups and which optionally comprise a saturated, partly saturated or aromatic 5 or 6 membered heterocyclic group which optionally comprises one or more heteroatoms and is optionally bears 1-3 subtituents independently selected from selected from the functional groups and/or the a lower alkyl ; accordingly non limiting examples include (furfuryl) alkyl, (hydroxyfurfuryl) alkyl, (imidazolyl) alkyl, (methylimidazolyl) alkyl, benzyl, benzyloxymethyl, 4-carboxymethoxybenzyl, 4-methoxybenzyl, 4-ethoxybenzyl,

4-butoxybenzyi, 4-benzyloxybenzyl, 4- (4-methyloxybenzyloxy)-benzyl ; methyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl, pentyl, cyclopentyl, cyclohexyl, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl)-ethyl, 3-hydroxypropyl, 2-hydroxy-isobutyl, 2, 3-dihydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl and 4-hydroxybutyl, 2-, 3-and 4-hydroxy-2methylbutyl, 2,3, 4-trihydroxybutyl, 2,3, 4,5, 6-pentahydroxyhexyl.

As examples of the CA-moieties of formula 10 or 11 which do not comprise a thiol function (-SH), are cited the organyl or organohetryl derivatives of iminoalkyl acids having carboxy methyl groups (-CH2COOH and-CH2COORz) as predominant aminyl Z-substituents: - ethylenediaminetetraacetic acid, diethylene triaminopentaacetic acid, triethylene tetramine

hexaacetic acid, trans-1, 2-cyclohexanediamine tetraacetic acid, 1, 4, 7, 10-tetraazacyclododecane tetraaceticacid, 1, 4, 7-triazacyclononanetriacetic acid, 1, 4, 8, 11-tetraazatetradecanetetraacetic acid, 1, 5, 9-triazacyclododecanetriacetic acid, - analogues in which one or more carboxy methyl groups are replaced by hydrogen or by another aminyl Z-substituent so that Z together with the aminyl group (referred to as amino) to which it is attached comprises, among a variety of other compounds: aminoethanol, 2-amino-2-ethyl-1, 3-propandiol, 3-methyl-1-butamine,

6-amino-2methyl-2-heptanol, 2- (2-aminoethoxy) ethanol, 1- (3-aminopropyl) imidazole, 4- (3-aminopropyl) morpholine, 1- (3-aminopropyl)-2-pipecoline, 1- (3-aminopropyl)-2-pyrrolidinone, 1- (2-aminoethyl) pyrrolidine, 1- (2-aminoethyl) pyrrolidine, 1- (2-aminoethyl) piperidine, 2- (2-aminoethyl) pyridine, 2- (aminomethyl) pyridine, 1- (2-aminoethyl) pyrrolidine, 4- (2-aminoethyl) morpholine, 4- (2-aminoethyl)-1-methylpyrrolidine, (aminomethyl) cyclopropane, 2- (aminomethyl) pyridine, 3-(aminomethyl)pyridine,

2- (aminomethyl)-1-ethylpyrrolidine, furfurylamine, tetrahydrofurfurylamine, 2- (aminomethyl)-tetrahydropyran, 2- (aminomethyl)-1, 3-dioxolane, 2- (aminomethyl)-1-methylimidazole, N- (2-aminoethyl) piperidine, N- (2-aminoethyl) morpholine, 3- (2-aminoethyl) indole, natural occuring aminoacids (D, L and DL) and analogues thereof, such as for example glycine (equivalent to carboxymethyl Z-substituent), leucine, isoleucine, isoleucinol, alanine, 0-alanine, valine, tyrosine, serine, threonine, and the like as well as their carboxamide (-C (=O)-NH2,-C (=O)-NH-Rzd1,-C (=O)-N (-Rzd2)-Rzd1), hydrazide - C (=0)-NH-NH-Rzh1 and-CH2C (=O)-NH-N (-Rzh2)-Rzh1) and ester (-C (=O)-Orz) accordingly suitable examples of such analogues are, N- (2-hydroxyethyl) diethylenetriamine N, N', N", N"'tetraacetic acid, N- (2-hydroxyethyl) ethylenediamine N, N', N"triacetic acid, Among the CA-moieties of formulae 10 and 11, especially prefered are the structures of formulae 10a-10gand11aand11b

whereby the arrows indicates the bonding position, including a-bond referring to the fact that the cheating agent is directly attached to the joined ring system A and ring system B (ss-CA is equivalent to the substituents C1, C2 or C3 of the general formula 1); and a 8-bond referring to the fact that the cheating agent is attached to the joined ring systems via a bivalent chain P-K-8, in this case ss-K-o-CA represents the C-functions C1, C2 or C3; Rz is as described hereinbefore, Suitable bivalent molecule portions K can be selected from the molecule portions referred to as Li.

Substituents of the ringsystem A, of the ringsystem B, and of the linking agent Li are hereinbelow referred to as W1, W2 and W3, respectively. In general they are referred to as W, whereby W not only refers to the the optional R substituents (R1, R2 and R3) in formula 1 but also to the substituents of precursor compounds. Indeed, W-substituents of precursor compounds may be used for example, possibly after optional adequate chemical modification, for enabling the attachment of C-function (s), for enabling a joined ringsystem A and ringsystem B, they may represent a temporary protected R-substituent and so on. Hence, W-substituents not only include the R-substituents but also comprise, among a variety of other substituents, reactive groups and atoms, activated groups, protected groups, protected R-substituents and the like.

A W-substituent is of the general formula 12: ss-W Formula 12 whereby the bond ss refers to the bond through which the substituent is attached to a joined ringsystem A and ringsystem B as in the compounds comprising formula 1 or in precursor compounds thereof; W is a substituent independently selected from the list comprising: halogens; organyl groups; organohetryl groups including organyloxy, organylaza and organylthio ; 0-functional groups and/or radicals comprising for example the hydroxyl (-OH), the oxo (=O), the allyl (-CH2-CH=CH2), the vinyl (-CH=CH2), the thiol (-SH), the thio (=S), the thiocyanato (-SCN),

the nitryl (-NO2), the nitrosyl (-NO), the aminyl (-NH2), the iminyl (=NH), the hydrazinyl (-NH-NH2), the azidyl (-N3), the ss-oxoacid such as for example carboxyl (-C02H), sulphono (-S03H) and phosphono (-P (=O) (OH) 2), the cyanyl (-CN), the sulfamino (-NHS03H), the allophanoyl (-C (=O)-NH-C (=O)-NH2), the guanyl (-C (=NH) -NH2), the acetyl (-C (=O)-CH3), the carboxyl (-COOH), the carboxamide (-C (=O)-NH2), the carboxamidine (-C (=NH) -NH2), the formyl (-C (=O)-H), the formamidyl (-NH-C (=O)-H), phosphonooxy (-O-P (=O) (OH) 2) and the like functional groups and/or radicals. Among the organyl and organohetryl groups of formula 12, preferred are the substituents having a structure according to formulae 13,14 15.

ss-A-[J]a-[A]b-I Formula 13 ss-[J]c-I"-I Formula 14 P-J- [A] d-' Formu) a15

ss-A-G-I Formula 16 P-G-I Formula 17 P-G- [F] r [A-I] e Formula 18 0-1 Formula 19 wherein P stands for a bond as described hereinabove; the indices a, b, c, d, e and f are in the meaning of the numerals 0 or 1 indicating abcence and precence, b is in the meaning of 1 provide that a is not 0, e and f are mutually exclusive 0 or 1;

A stands for an acyl moiety, freely selected from the list essentially comprising carbonyl (-C (=O)-), thioyl (-C (=S)-), sulfonyl (-S (=0) 2-), sulfonyl (-S (=O)-), imidoyl (-C (=NH)- and - C (=N-)")-) ; J stands for an aminyl moiety (-NH-,-N (-)')- or-N (-)")-) or an hydrazo (-NH-N H-, -NH-N(-I")-, or -N(-I')-N(-I")-); - J"stands for-N=CH-and-N=C (-I")- - G stands for an oxygen (-0-) or a sulfur atom (-S-) ; - F stands for a moiety-S (=0) 2-O-I', -S (=O)-OH, -S (=0) O-I', -S (=O)-l',-N02,-NO, -P(=O) (-OH) 2, -P (=0) 2 (-O-I'),-B (-OH) 2 and the like ; I and the optional 1"stand for a straight-chain or branched-chain, cyclic or partly cylic, saturated, partly unsaturated and/or aromatic or partly aromatic hydrocarbyl radical, which is optionally substituted by halogens and/or by one or more of the aforementioned functional groups or atoms and/or optionally comprises one or more heteroatoms, including moieties herein referred to as A, J or combinations thereof. Optionally, the I substituent together with an l"substituent may form a saturated or partly unsaturated hetero cyclic ring skeleton,

which optionally bears one or more, optionally substituted, fused saturated, partly unsaturated and/or aromatic rings that optionally comprise one or more hetero atoms ; when the indiches a and b of formula 13 are in the meaning of 1, the molecule portion- [J] ameans hydrazo ; when the index c of formula 14 means 1, then J means-NH-or-N (-1')- ;

W substituents of formula 13 include the ss-A-I, the ss-A-J-I and the ss-A-J-A-I acyl-type substituents ; whereby ss-A-in the meaning of carbonyl (-C (=O)-) and sulfonyl (-S (=0) 2-) are preferred.

As examplary (3-A-I acyl-type substituents are cited : 5-bromothiophenesulphonyl, 5-chlorothiophenesulphonyl, 2-thiophenesulfonyl ; 4-fluorobenzenesulfonyl, 2-mesitylenesulfonyl, 4-methoxybenzenesulfonyl, p-toluenesulfonyl, pentafluorobenzenesulfonyl, benzenesulfonyl, 4-bromobenzenesulfonyl, N-acetylsulfanilyl, 2, 4, 6-triisopropylbenzenesulfonyl, 4-chlorobenzenesulfonyl, 3, 5-dichloro-2hydroxybenzenesulfonyl, a-toluenesulfonyl, 2, 5-dichlorobenzenesulfonyl, pipsyl, methyl 2 (chlorosulfonyl) benzoate, 4-tert-butylbenzenesulfonyl, 3- (trifluoromethyl) benzenesulfonyl, 2 bromobenzenesulfonyl, 2- (4-chlorosulfonylphenyl) ethyltrimethoxysilane, 4-acetylbenzenesulfonyl, 4-chloro-3-nitrobenzenesulfonyl, 4- (chlorosulfonyl) benzoic acid, 3- (chlorosulfonyl) benzoyl, 2, 4-dinitrobenzenesulfonyl, 3-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2-methylsulphonylbenzenesulphonyl, 4-methylsulphonylbenzenesulphonyl dansyl, 2-naphthalenesulfonyl, 1-naphthalenesulfonyl ; 1-hexadecanesulfonyl, methanesulfonyl, 3-chloropropanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2, 2, 2-trifluoroethanesulfonyl, octanesulfonyl, 1-butanesulfonyl, 2-chloroethanesulfonyl ; cyclobutanecarbonyl, cyclopropanecarbonyl, 2-furoyl, cyclohexanecarbonyl, 2-thiophenecarbonyl, isonicotinoyl, 2-thiopheneacetyl, 2, 6-dichloro-5-fluoronicotinoyl, nicotinoyl, 7- [ (chlorocarbonyl) methoxy]-4-methylcoumarin ; p-anisoyl, benzoyl, 2-bromobenzoyl, 4-bromobenzoyl, 3-chlorobenzoyl, 2, 6-dimethoxybenzoyl, pentafluorobenzoyl, 2-chlorobenzoyl, p-toluoyl, 4-chlorobenzoyl, 2, 4-dichlorobenzoyl, 3, 4-dichlorobenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 2-fluorobenzoyl, m-/o-toluoyl (-CO-C6H5CH3), 4-cyanobenzoyl, 3-nitrobenzyl, 4-tert-butylbenzoyl, 3, 5-dimethoxybenzoyl, 3-Fluorobenzoyl, m-anisoyl, 2, 6-difluorobenzoyl, 2-nitrobenzol 4-chloro-3-nitrobenzoylchloride, 3, 4-difluorobenzoyl, 2-iodobenzoyl, o-anisoyl, 2, 4-difluorobenzoyl, 4- (trifluoromethyl) benzoyl, 3, 5-bis (trifluoromethyl) benzoyl, 3, 4-dimethoxybenzoyl, 4-ethylbenzoyl, 3-methoxyphenylacetyl,

4- (trifluoromethoxy) benzoyl, 3, 5-difluorobenzoyl, 2, 4, 5-trifluorobenzoyl, 2, 5-difluorobenzoyl, 4-decylbenzoyl, 3, 5-dinitrobenzoyl, 4-heptylbenzoyl, 4-iodobenzoyl, 4-octylbenzoyl, 4-pentyloxybenzoyl, 4-propylbenzoyl, methyl 4-chlorocarbonylbenzoate ; mandelyl (-CO-CH (OH) C6H5), methacrylyl (-CO- (CH3) C=CH2), O-acetylmandelic acid, 2-chloro-2, 2-diphenylacetyl, cinnamoyl, 4-chlorobenzeneacetyl, phenylacetyl, hydrocinnamoyl, 1- (4-chlorophenyl)-1-cyclopentanecarbonyl, D/L-2-chloro-2-phenylacetyl, phenoxyacetyl, 4-biphenylcarbonyl, (S)- (+)-a-methoxy-a-trifluoromethylphenylacetyl, (R)- (-)-a-methoxy-a-trifluoromethylphenylacetyl, 1-naphthyl, diphenylacetylchloride, 2- (trifluoromethyl) benzoyl, 3- (trifluoromethyl) benzoyl, 4-isocyanaobenzoyl, 3- (chloromethyl) benzoyl, 4- (chloromethyl) benzoyl, 3- (dichloromethyl) benzoyl, 2, 3, 4, 5-tetrafluorobenzoyl, 2, 4, 6-trichlorobenzoyl, 2-phenylbutyryl, 2- (4-nitrophenoxy) tetradecanoyl ;

10-undecenoyl, 2-bromo-2-methylpropionyl, 2-bromopropionyl, 2-chloropropionyl, 2-ethylbutyryl, 2-ethylhexanoyl, 3, 3-dimethylacryloyl, 3-bromopropionyl, 3-chloropivaloyl, 3-chloropropionyl, 4-bromobutyryl, 4-butylbenzoyl, 4-chlorobutyryl, 4-heptyloxybenzoyl, 4-hexylbenzoyl, 4-hexyloxybenzoyl, 4-pentylbenzoyl, 5-chlorovaleryl, 6-bromohexanoyl, acetyl, acryloyl, adipyl (-CO- (CH2) 4CO2), bromoacetyl, butyryl (-CO- (CH2) 2CH3), chloracetyl, decanoyl (-CO- (CH2) 8CH3), dichloroacetyl, D/L-2-ethylbutyryl, ethyl malonyl, ethyl oxalyl, ethyl succinyl, fumaryl, heptafluorobutyryl, heptanoyl, hexanoyl (-CO- (CH2) 4CH3), hydantoyl (-CO-CH2NHCONH2), isobutyryl, isovaleryl chloride (-CO-CH2CH (CH3) 2), ) acty) (-CO-CHOHCHs),'auroy ! (-CO- (CH2) ioCH3),) evu) iny) (-CO- (CH2) 2COCH3), linolenoyl, linoleoyl, methacryloyl, methoxyacetyl, methyI4- (chloroformyl) butyrate, methyl oxalyl, myristoyl, myristyl (-CO- (CH2) i2CH3), nonanoy ! (-CO- (CH2) 7CH3), octanoy) (-CO- (CH2) eCH3), oleoyl (-CO- (CH2) 7CH=CH (CH2) 7CH3), palmitoyl (-CO- (CH2) 14CH3), propionyl (-CO-CH2CH3), sorbyl (-CO-CH=CHCH=CHCH3), stearyl (-CO- (CH2) ieCH3), tert-butylacetyl, trans-crotonyl, succinamyl (-CO-CH2CH2CONH2), trichloroacetyl, trimethylacetyl, valeryl (-CO- (CH2) 3CH3) ;

The ss-A-J-I amide and hydrazide-type substituents comprise the substituens which can be conceptually derived by replacing-OH* from a ss-oxoacid substitent, such as for example a ss-carboxyl group (ss-C (=O)-OH*) or a ss-sulfonyl group (ss-S (=0) 2-OH*), by a radical derived by extracting a proton (H*) from a primary amine (*H-NH-I), a secondary amine (*H-N (-I")-I) or a hydrazine (*H-NH-NH-I and *H-NH-N (-I")-I). As already mentioned the optional radical 1"and the radical I may form a heterocyclic ring around the N-atom to which they are attached. Accordingly,

ss-A-J-I amide and hydrazide-type substituents comprise for example : ss-C (=O)-NH-I, ss-C (=O)-N (-I")-I and ss-C (=O)-N (-ici whereby I and 1"form an heterocyclic ring, ss-C (=O)-NH-NH-I, ss-C (=O)-NH-N (-I")-I and ss-C (=O)-NH-N (-I")-I whereby I and 1"form an heterocyclic ring, ss-S (=0) 2-NH-I, ss-S (=0) 2-N (-I")- ! and ss-S (=0) 2-N (-I")-) whereby I and 1"form an heterocyclic ring, ss-S (=0) 2-NH-NH-I, ss-S (=0) 2-NH-N (-I")-t and ss-S (=0) 2-NH-N (-I")-) whereby I and 1"form an heterocyclic ring.

Examplary ss-A-J-I amide and hydrazide-type substituents can be conceptually derived from either a ss-carboxyl group or a ss-sulfonyl group (ss-S (=0) 2-OH*) and a compound bearing an *H-nitrogen proton. Suitable examples of latter can be selected from the following listing but are, however, not limited to the listed: primary amines (*H-N (H)-I), such as for example primary amines known to occur as primary amines of formula, including natural amino acids and analogues thereof as well as derivatives bearing protected functional groups; secondary amines (*H-N (-I")-I) such as for example secondary amines known to occur as secondary amines of formula ; - secondary amines (*H-N (-I")-I) whereby the substituents together with the nitrogen form a heterocyclic ring skeleton (for example a piperidine, morpholine, piperazine and the like skeletons); - hydrazines (*H-NH-NH-))) such as for exampe hydrazines known to occur as hydrazines of formula ; - N-substituted hydrazines (*H-NH-N (-I")-I)), such as for example N-substituted hydrazines known to occur as hydrazines of formula ; - N-substituted hydrazine like compounds (*H-NH-N (-I")-I) whereby the nitrogen is part of an heterocyclic ring) ;. ), such as for example N-substituted hydrazine like compounds known to occur as hydrazines of formula The ss-A-J-A-I bis acylhydrazide-type substituents comprise the substituens which can be conceptually derived from a ss-oxoacid substitent, such as for example a 0-carboxyl group

(ss-C (=O)-OH*) or a ss-sulfonyl group (ss-S (=0) 2-OH*), by replacing hydroxyl (-OH*) by a radical obtained by extracting a proton (H*) from a hydrazide (*H-NH-NH-A-I and *H-NH-N (-I")-A-I), including carbohydrazide, sulfonohydrazide and phosphonichydrazides.

Accordingly, ss-A-J-A-I bis acylhydrazide-type substituents comprisefor example:

ss-C (=O)-NH-NH-C (=O)-I, ss-C (=O)-NH-N (-I")-C (=O)-I, P-S (=0) 2-NH-NH-C (=O)-I, ss-S (=0) 2-NH-N (-I")-C (=0)-), ss-S (=0) 2-NH-NH-S (=0) 2-1, and ss-S (=0) 2-NH-N (-I")-S (=0) 2-1 groups.

Examplary P-A-J-A-1 bis acylhydrazide-type substituents can be conceptually derived from either a ss-carboxyl group or a ss-sulfonyl group (ss-S (=0) 2-OH*) and an *H-nitrogen proton bearing hydrazide. Suitable examples of latter can be selected from the following listing but are, however, not limited to the listed : the hydrazide analoges of the aforementioned ss-A-I acyl-type radicals, derived by replacing a proton (H**) from either hydrazine (H-NH-NH-H**) or N-substituted hydrazine (H-N (-I")-NH-H**) by ss-A-I acyl-type substituent, including the exemplary ss-A-I acyl-type substituents cited hereinabove.

W substituents of formula 14 refer to the ss-J"-I iminyl type and the ss-J-J"-I hydrazo type substituents; including aldimidyl (ss-N=CH-I) and ketimidyl (ss-N=C (-I")-I) substituents as well as hydrazo substituents of formulae ss-NH-N=CH-I, ss-N (-I')-N=CH-I, ss-NH-N=C (-I")-I and ss-N (-I')-N=C (-I")-I. Aldimidyl and ketimidyl substituents are formally derived by replacing the oxo (0=) from aldehydes and ketones, respectively, by ss-N= obtained by extracting two protons from the amino functional group (ss-NH2). Likewise, the hydrazo substituents are formally derived from aldehydes and ketones by replacing the oxo (0=) by ss-NH-N= or ss-N (-I')-N= obtained by extracting two protons from the hydrazyl sustituent (ss-NH-NH2) or its N-substituted analogue (ss-N (-I')-NH2), respectively.

Accordingly, examplary substituents can be derived from either a p-amino function (ss-NH2) or an, optionally N-substituted, ss-hydrazyl group ( (P-NH-NH2 and ss-N (-I')-NH2) and aldehydes and ketones. Examplary aldehydes and ketones can be selected from the following listing but are, however, not limited to the listed : - suitable aldehydes are aldehydes occurring as aldehydes of formula, including optionally oxidized (periodate) carbohydrates - suitable ketones are ketones occurring as aldehydes of formula.

W substituents of formula 15 include the ss-J-I aminyl, ss-J-I hydrazyl, ss-J-A-I amide and ss-J-A-I hydrazide type substituents; whereby-A-in the meaning of carbonyl (-C (=O)-), sulfonyl (-S (=0) 2-) and are preferred. The ss-J-I aminyl type substituents of formula 15 can be formally derived by replacing one or two protons of a p-amino substituent (ss-NH2) with an lot an I and I"organyl type radical, giving N

substituted (ss-NH-I) and N, N-substituted (ss-N (-I")-I) ss-aminyl groups, respectively. Likewise, the ss-J-I hydrazyl type substitents ss-NH-NH-I, ss-NH-N (-I")-I, ss-N (-I')-NH-I and ss-N (-I')-N (-I")-I are derived by replacing one or more protons of a ss-hydrazyl group (ss-NH-NH2) with an I, I'and/or I" organyl type radical. Formal hydrogenation of the double bond (-C=N-) occurring in the aforementioned ss-J"-I iminyl type (ss-N=C) and the ss-J-J"-I hydrazo type (ss-NH-N=C, ss-N (-I')-N=C) substituents will also afford the substituent groups.

Examplary ss-J-I aminyl type substituents according to formula 15 of formulae ss-NH-I and ss-N (-I")-I comprise: - aminyl substituents whereby I and the optional 1"represent a organyl radicals selected from the list comprising substituents known to occur in secondary and tertiary amines of formula; - substituents derived by hydrogenation of the double bond (-C=N-) occurring in the aforementioned ss-J"-I iminyl type (ss-N=C) substituents, including the cited examples thereof; - N, N substituted aminyl substituents whereby and I" together with the nitrogen atom form an heterocyclic ring such as for example substituents known to occur in tertiary cyclic amines of formula. Exemplary ss-J-I hydrazyl type substituents according to formula 15 of formulae ss-NH-NH-I,

ss-NH-N (-I")-I, ss-N (-I')-NH-I and ss-N (-I')-N (-I")-I comprise - hydrazyl substituents of formulae whereby I'preferably stands for lower alkyl, aralkyl or aryl such as for example C1-C5 alkyl, including methyl, ethyl, phenyl and benzyl, and I and I" represent organyl radicals as described for the preceding aminyl substituents; - substituents derived by hydrogenation of the double bond (-C=N-) occurring in the aforementioned ss-J-J"-I hydrazo type substituents, including the cited examples therewithin; - N', N'-substituted hydrazyl groups whereby I and 1"together with the nitrogen atom form an heterocyclic ring such as for example known to occur in hydrazyl groups of formulae. The ss-J-A-I amide type substituents of formula 15 include both the monoacyl (amides) and diacyl (imides) substituents. The ss-J-A-I amides can be formally derived by replacing one proton of a (3-amino substituent (ss-NH2 or ss-N (-I') H) by an acyl radical (-A-I), whereby-A-is preferably in the meaning of carbonyl (-C (=O)-) and/or sulfonyl (-S (=0) 2-). Examplary ss-J-A-I amide type substituents according to formula 15 of formulae ss-NH-C (=O)-I,

P-N (-I')-C (=O)-I, ss-NH-S (=0) 2-1, ss-N (-I')-S (=0) 2-1, and ss-N (-I")-I comprise the substituents derived from a p-amino group (ss-NH-H*) or an N-substituted p-amino group (ss-N (-I')-H*) by replacing the aminyl H* proton by an acyl radical of formula -A-I as described hereinabove under the previous heading dealing with ss-A-I acyl type substituents, including the cited examples thereof.

The ss-J-A-I hydrazide type substituents of formula 15 can be formally derived by replacing one proton (H*) of a ss-hydrazyl substituent (ss-NH-NH-H* or ss-N (-I')-NH-H*) by an acyl radical of formula -A-I ; Examplary ss-J-A-I hydrazide type substituents comprise the substituents derived from a ss-hydrazyl group (ss-NH-NH-H* or ss-N (-I')-NH-H*) by replacing the hydrazyl H* proton by an acyl radical of formula -A-I as described hereinabove under the previous heading dealing with ss-A-I acyl type substituents, including the cited examples thereof.

W substituents of formula 16 include ester-type substituents of formula ss-A-G-I ; whereby ss-A-is preferably in the meaning of carbonyl (-C (=O)-), sulfonyl (-S (=0) 2-), thioyl (-C (=S) -) and-G-in the meaning of oxygen (-0-) or sulfur ; the substuent portions ss-A- and -G- in the meaning of carbonyl and oxygen, respectively, are especially preferred. Hence, formula 16 include the ester-type

groups of formulae ss-C (=O)-O-I, ss-C (=S)-O-I, p-C (=O)-S-I and ss-S (=0) 2-0-1.

Examplary ester-type substituents of formula ss-A-G-I can be formally derived from a ss-oxoacid functional group (such as for example ss-C (=O)-OH, P-S (=0) 2-OH, and the like) and an alcohol, a phenol, a heteroarenol, enol or their chalcogen (thiol) analogues by linking with formal loss of H20 from an acidic hydroxy group of the oxoacid and a hydroxy group of the latter. Accordingly, as non limiting examples can be cited: the esters derived from a ss-carboxylic acid functional group (ss-C (=O) OH) and hydroxy or thiolbearing compounds such as for example - optionally by halogens and or functional groups, including lower alkyl, aralkyl and aryl, substituted alkyl alcohols or aralkyl alcohols as well as their thiol analogues, which comprise esters known to occur in esters of formula ; optionally by halogens and or functional groups, including lower alkyl, aralkyl and aryl, substituted phenol or heteroarenol as well as their thiol analogues, which comprise the phenol compounds and heteroarenols known to occur as such. optionally by halogens and or functional groups, including lower alkyl, aralkyl and aryl, substituted enols well as their thiol analogues, which comprise among a variety of other compounds: the enol compounds and their thiol analogues known to occur as such, including carbohydrates.

W substituents of formula 17 include (thio) ether-type substituents of formula ss-G-I, whereby the substituent portion ss-G-is in the meaning of oxygen (-0-) or sulfur (-S-) Examplary ether-type substituents of formula ss-A-I can be formally derived from a ss-hydroxyl (ss-OH) or a ss-thiol (ss-SH) functional group and an alcohol, a phenol, a heteroarenol, enol by linking with formal loss of H20 from the 0-functional group and the hydroxy group of the latter.

Accordingly, exemplary (thio) ether-type substituents of formula ss-G-I can be formally derived from a p-hydroxy ! (p-OH) or a ss-thiol (ss-SH) functional group and an hydroxy compound selected from the examples listed under the preceding heading which describes ester-type substituents of formula ss-A-G-I according to formula 16.

W substituents of formula 18 include ester-type substituents of inorganic and organic acids of formulae ss-G-F and ss-G-A-I, whereby the substituent portion ss-G-is in the meaning of oxygen (-0-) or sulfur (-S-) ; F is selected from the list comprising the groups-S (=0) 2-O-I', -S (=O)-OH, - S (=0) 0-1',-S (=0)-i',-N02,-NO,-P (=O) (-OH) 2,-P (=0) 2 (-0-lib (-OH) 2 and the like ; A is preferably carbonyl (-C (=O)-) or sulfonyl (-S (=0) 2-).

Regarding the esters of inorganic acids of formula ss-G-F, G in the meaning of oxygen is preferred.

According examples include the following ss-W substituents : ss-O-S (=0) 2-0-l', ss-O-S (=O)-OH, ss-O-S (=O) O-I', ss-O-S (=O)-I', ss-O-NO2, ss-O-NO, ss-O-P (=O) (-OH) 2, p-0-P (=0) 2 (-O-I'), ss-O-B (-OH) 2, whereby I'is selected from the aforementioned lower alkyl, aralkyl and aryl groups.

Regarding the esters of formula ss-G-A-I, G in the meaning of oxygen or sulfur are preferred ; the substituent portion-A-preferably means carbonyl (-C (=O)-) or sulfonyl (-S (=0) 2-). Hence, formula ss-G-A-I include the ester-type groups of formulae ss-O-C (=O)-I, p-S-C (=O)-I, P-0-S (=0) 2-1.

Examplary esters of formulae can be formally derived from a ss-hydroxyl (ss-OH) or a ss-thiol (ss-SH) functional group and replacing the hydroxyl or thiol proton by an acyl radical of formula-A-) as described hereinabove under the above heading dealing with ss-A-I acyl type substituents, including the cited examples thereof. Further examples may be formally derived from a ss-hydroxyl (ss-OH) or a ss-thiol (ss-SH) functional group and an organic carboxyl acid by linking with formal loss of H20 from the former groups and the acidic hydroxy group of the carboxylic acid. Among the variety of possible examples tosylester (-O-S (=0) 2-C6H4-CH3) and the borosylester (-O-S (=0) 2-C6H4-Br) are especially useful.

W substituents of formula 19 (ss-l) include, optionally by halogens and/or functional groups substituted, alkyl, aralkyl and aryl substituents. For obvious reasons, examples of the substituent portion-I can be deduced from the under all preceding headings described formulae (formula 13 to 18), including the accompanying examples therewithin.

It will be obvious to one of skill in the art that compounds embodying the novel general formula 1 can be disconnected in terms of precursor compounds and chemical reactions in numerous ways.

Therefore the hereinbelow in detail described methods and examplary pathways for obtaining the novel compounds should not be construed as limiting the scope of the present invention. Altough a multitude of routes enable organic synthesis of the novel compounds, preferred are those pathways whereby a at least one precursor compound matches one of the two ring systems or the pathways according to wich a precursor compound essentially akin to ring system A is conjugated with a precursor compound essentialy akin to ring system B.

Suitable ring system precursors may be available from commercial resources or can be synthesized exercising methods and literature reports known to one of ordinary skill in the art.

Precursor ring systems that already bear the finally required substiuents or primordial forms thereof are preferred when consecutive conjugation steps may involve bonds which are vulnerable towards the possible harish conditions required for introducing the substituents of choice. Precusor compounds essentially akin to an up linked ring system A and ring system B can be provided according to either a one step or a multistep procedure. The latter involves for example derivatization of precursor ring system A compound and establishing a bond (see above) by conjugation with a suitable linking agent precursor and isolation of the adduct. Next, either a ring system B is assembled making use of molecule portions of the adduct or the adduct, after optional derivatization, is conjugated with a ring system B precursor.

Single step procedures include both procedures that enable direct bond formation between for example an aromatic ring of a precursor ring system A and an aromatic ring of ring system A (see e. g. Ullmann coupling, phenolic oxidative coupling, and the like in e. g. Smith M. B 1994, Organic Synthesis, 1595p McGraw-HiH,) nc. New York) as well as procedures that enable synthesis of compounds according to formula 1 characterized by the presence of molecule portion referred to as linking agent. The latter type single step procedures are very suitable for linking two precursor ringsystems and, moreover, enable the introduction of assymmetric linking agents in the compounds.

According to a first approach an examplary precursor ring system A comprising a nitrogen atom of formula-NH- (other than the optionally S1 substituted nitrogen of formula 1) in its skeleton, or which bears a primary or secondary amino function either as a 0-functional group (for example the ss-NH2, the ss-N-NH2, the-p-C (=O)-NH-NH2, and the like groups) or as an optional substituent of a ss-W1 group, can be coupled with a precursor ring system B which bears a carboxyl function either as a ss-functional group (ss-COOH) or as optional substituent of a ss-W group. Such coupling reactions routinely involve condensing agents such as for example N, N'-dicyclohexyl carbodiimide (DCC), N, N'-carbonyldiimidazole, N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ), 2-isobutoxy-1-isobutoxycarbonyl-1, 2-dihydroquinoline (IIDQ) and the like. Provided optionally present additional reactive groups are adequately protected (see e. g. Greene T. W. & Wuts P. G. M, 1999, Protective groups in organic synthesis 3th edition, J. Wiley & Sons, Inc. New York) these coupling reactions are very useful.

Another line of approach involves the use of homo bifunctional linking agent precursors As used herein homobifunctional linking agent precursors comprise: symmetric or asymmetric optionally by halogens and or functional groups (adequately protected if required) substituted straight chain, branched chain, cyclic or partly cyclic saturated, partly unsaturated, partly aromatic or optionally aromatic - bisamines such as for example alkyl diamines of formula H2N- (CH2) 2-12-NH2 including 1,2-diaminoethane, 1,5-diaminopentane 1,6-diaminohexane, 1,7-diaminoheptane 1,2-diaminododecane and the like, alkyl diamines comprising one or more hetero atoms such as for example 1,8-diamino-3. 6-dioxaoctane, 1,5-diamino-3-oxapentane, alkyl diamines comprising one or more optionally protected functional groups such as for example lysine and lysine ; cyclic bis amines such as for example piperazine and derivatives thereof; - bis oxyranes; - bis anhydrides, including mixed anhydrides and bis anhydrides of general formula 3; bis hydrazides such as for example succinic dihydrazide, adipic dihydrazide and the like hydrazides; bis acyl halides (chlorides are preferred); bis formyl compounds;

bis carboxylates and activated esters thereof.

These homobifunctional linking agent precursors allow to introduce both symmetric and asymmetric linking agents which up link both ring systems via a-and M-bonds of the same formal bond type, this holds true provided that the functional groups of both ring systems involved in up linking are comparable or identical. However, if a W1 ss-carboxyl group is for example condensated with a W2 ss-propionate substituent (ss-CH2-CH2-COOH) using ethylenediamine as the bifunctional linking agent precursor, then the linking agent will be of formula a-C (=O)-NH-CH2-CH2-C (=O)-NH-CH2-CH2-M. Consequently the a-bond and the m-bond are formally of different kind.

The methods for up linking discribed thus far, enable synthesis of precursor compounds in which both ring systems are either joined together by means of a direct link or a multi atom spacer (see howerer the cases whereby for example amide formation involves a ss-carboxyl group of one ring system and a nitrogen atom of formula-NH-as part of skeleton of the other ring system). If a single atom spacer, in particular substituted derivatives thereof, is wanted the previous methods are of little use. However, the condensation of aromatic rings with aldehydes or ketones, referred to as hydroxyalkylation or hydroxyalkyl-de-hydrogenation (see e. g. March J.; Advanced Organic Chemistry, 3th edition 1985, J. Wiley & Sons, New York), enables compounds comprising general formula 1, whereby ring system A and ring system B are joint by a methylene bridge. Because both aliphatic as well as aromatic aldehydes and ketones may be used as linking agent precursor, the diarylation reaction is usfull for linking two ring systems and simultaneously introducing a mulitude of W3-type substituents.

Once a precusor compounds essentially akin to an up linked ring system A and ring system B is available a cheating agent molecule portion (CA of formula 7) can be introduced. This can be achieved for example by making use of a precursor CA compound. As used herein, precursor CA compounds include but are not restricted to the well-known bifunctional cheating agents. The latter are compounds bear, beside the necessary functional groups (most often in shielded by protective groups) to enabel metal complexation), a functional group (often in an activated form; e. g. carboxylic esters comprising an appropriate leaving group) that can be specifically used in conjugation reactions. Accordingly, a bifunctional cheating agent is useful for introducing one or more CA-functions in the molecule. This can be accomplished by conjugating the bifunctional cheating agent directly to an atom which is part of the of ring skeletons or the linking agent (for example a nitrogen atom of formula-NH-). Otherwise, the bifunctional cheating agent can be conjugate to the molecule making use of a ss-W substituent. Optionally, one or more ss-W substituents present in the up linked precursor compound have to be chemically modified to enable reaction (removal of protective group (s), activation of a functional group) and/or to introduce a suitable spacer (akin to but not equivalent with molecule portion K of formula 7). A spacer molecule can be introduced in the molecule, or build up sequentially, in various ways. These include for example modification of one or more available ss-W substituents, introducing of one or more new P-W substituents and/or combinations thereof. Hereby one can make use of compounds hereinabove referred to as homobifunctional linking agent precursors (optionally with one of the

functions in a protected form) or their heterobifunctional analogues (e. g. 8-aminooctanoicacid as analogue of 1,7-diaminoheptane or azelaic acid) in an optionally protected form. Accordingly, an utterly examplary P-W substituent ss-C (=O)-NH-NH2 can be derived by coupling a 0-carboxyl group with tert-butyl carbazate and one of the condensing agents such as DCC, EDDQ and the like, followed by deprotection to make the hydrazide available for further reaction. The same examplary ss-W substituent can also be obtained by hydrazinolysis of a 0-carboxyl alkyl ester group with hydrazine. Hydrazinolysis, aminolysis and the like procedures are often appropiate alternatives for reactions involving condensing agents and precursors bearing protected functional groups which necessitate deprotection. However, both approaches have their merits.

Precursor compounds comprising for example hydrazine (H2N-NH-and substituted analoges), hydrazide (H2N-NH-C (=O)- and substituted analoges), primary and secondary amines (H2N-, HN (-)- included those part of a ringskeleton and/or part of the linking agent) and the like target functions are often particulary useful for introducing CA-function (s) by means of bifunctional cheating agents. Indeed, a vast majority of bifunctional cheating agents can be coupled to precursor compounds bearing these target functions. Often a carboxylic acid group (or an activated form of it) of the bifunctional cheating agent is involved in coupling. This is the case in bifunctional cheating agents bearing and intra molecular anhydride derived from, for example, an iminodiacetic acid molecule portion (-N (CH2COOH) 2). Examplary compounds comprise bis-anhydrides of EDTA, DTPA and the like (see e. g. French patent nr 1.548. 888, 1968 to J. R. Geigy S. A. disclosing the preparation of bisanhydrides by a pyridine/acetic anhydride method) as well as DTP Amonoanhydride ethylester.

The bis-anhydride of DTPA is not really a bifunctional agent because it has two activated carboxyl functions which can be involved in coupling reactions. Consequently, DTPA bisanhydride as such is hardly useful for introducing a CA-function because unwanted cross-linking reactions are almost unavoidable. Therefore, when DTPA is choosen to represent a CA-function, it is more appropriate to use a truely bifunctional derivative of it. Among the numerous bifunctional DTPA derivatives known from literature (see e. g. J. Org. Chem 1990,55, 2868; US5, 514, 810), DTPA monoanhydride ethylester is one of the most suitable. However, this monoreactive DTPA derivative is not commercially available. Nevertheless, DTPA monoanhydride ethylester has been employed in conjugation reactions; the compound is prepared by the well-known pyridine/acetic anhydride method (see above) from DTPA monoethylester. For the synthesis of this precursor molecule only a single article (viz. J. Pharm. Sci. 68 1979,194) is directly or indirectly cited (direct or indirect EP263059, DE19744003, US005284647 and particularly US6,083, 479 of Jul. 4 2000, to Schering A. G. ). Even after extensive experimentation we were unable to succesfully prepare DTPA monoethylester according to the disappointingly documented procedure described in J. Pharm.

Sci. 68 1979,194. A major reason why the published procedures for obtaining the reactive precursor DTPA monoanhydride monoethylester, turned out to be irreproducible originates from the fact that the most important aspect of the preparation scheme, viz. the procedure affording the physical separation of the title compound and the substantial amounts of byproducts (DTPA, DTPA mono ethyl ester and DTPA diethyl ester, was not reproducible and/or not disclosed.

Because the bifunctional cheating agents of general formula 2 are widely applicable, possible applications comprise for example their use as mono reactive CA-precursors, it is also an object of the present invention to provide compounds of general formula 2: Wherein V stands for a molecule portion as defined hereinabove (see CA-moieties of formula 10); s, t, u and v are integers independently selected from 1 to 3 provided that the sum of s and t and the sum of u and v is equal or smaller than 4; Vx and Vy are freely but mutually exclusively selected from either the group comprising-OH and-O"Cat (with Cat standing for an organic or inorganic cation, i. e a carboxylate salt) or from the group comprising : - radicals of formula-NH2; - radicals of formula-0-1 as essentially described hereinabove for ether-type W substituents (formula 17) of formula ss-G-I, whereby-G-is in the meaning of oxygen (-0-); - radicals of formula-NH-I and-N (-ill as essentially described hereinabove for aminyl-type W substituents (formula 15) of formula ss-J-I ; - radicals of formula-NH-NH-I,-NH-N (-I")-I,-N (-I')-NH-I and-N (-I')-N (-I")-I as essentially described hereinabove for hydrazyl type W substituents (formula 15) of formula ss-J-I ; - radicals of formula-NH-NH-I,-NH-N (-I")-I,-N (-l')-NH-I and-N (-l')-N (-I")-I as essentially described hereinabove for hydrazide type W substituents (formula 15) of formula ss-J-A-I with a preferentially in the meaning of carbonyl (-C (=O)-) or sulfonyl (-S (=0) 2-).

Accordingly Ux and Uy together with the carbonyl may stand for example for: a carboxylic acid, a carboxylate (salt with organic or inorganic cations), an amide (-CO-NH2), N-substituted amide, N, N substituted amide, an hydrazide, a bis acylhydrazide group.

After extensive experimentation it was found that the bifunctional chelating agents of formula 2 can be obtained by a procedure as outlined in the chart of figure 1 (fig1) of the present invention and as further described hereinbelow.

The bis anhydride analogue of formula 3 (I in fig1), obtained according to methods which are public property (see e. g. French patent nr 1.548. 888,1968 to J. R. Geigy S. A), is dissolved (with optional heating) in a suitable ahydrous solvent (for example DMF) or solvent mixture, in the presence of a base which does not react with anhydrides (for example a tertiary amine such as triethylamine).

Next, equimolar amounts of preferably an alcohol comprising one or more aromatic molecule portions (for example benzyl alcohol) and a coumpound which is known to react with anhydrides are added. If a maximal number of carboxylic groups is desired than the second reactant is preferably a lower alcohol (such as for example methyl, ethyl and the like alcohols) which can easily be removed by hydrolysis. If, on the other hand, a transformed carboxylic moiety is desired than the second reactant is preferably selected from the list comprising: amino, hydrazino and hydrazide compounds. Even if reaction conditions are optimal with respect to temperature, dilution and the way both reactans are indroduced (simultaneous, as a diluted mixture, one after the other, dropwise, etceteras), the fraction of the two major side products (bis reactant1 ester and bis reactant 2 derivative of the bis anhydride) will be substantial. Hence, a second step (fig1) involves the physical separation of the three major reaction products. Selecting the first mentioned reactant based on the presence of aromatic moeities enables purification under mild conditions, i. e. for example non-hydrolytic conditions with respect to lower alkyl esters) using methods that allow separation based on differences in hydrophobicity and type of hydrophobic interaction. These methods may include extraction based procedures, chromatographic procedures using reversed phase chromatography on alkylated solid supports, chromatographic procedures employing adsorbtion chromatography on polymeric supports, and so on. Fractions containing essentially pure compound (of formula 11 in fig1, wherein B1 and B2 mutually exclusive represent either a proton or the non hydroxyl portion of the alcohol used as reactant 1) are further processed, this involves the selective removal of the B-substituent (step 3) to afford compound comprising a shielded terminal imino bis alkylcarboxylic acid molecule portion and an unprotected counterpart which, in a final step (step 4) is converted to the desired anhydride of formula 2 (IV in fig1).

A specific embodiment of the novel procedure is found examples 1 to 3 hereinbelow, these examples enable the preparation of essentially pure DTPA monoethylester monoanhydride, which was proved to be suitable for introducing one or more cheating moieties CA in intermediate compounds enabling compounds comprising formula 1.

Accordingly, it is also an object of the present invention to provide mono reactive DTPA derivatives according to the newly invented procedure and use the product as a precursor compound for introducing CA-functions.

For some applications (e. g. preparation of compounds comprising alkaline and/or acidic labile substructures, etc. ) it is beneficial to accomplish coupling with DTPA comprising unprotected carboxyl group (s) (e. g. devoided of ester groups) because removing the protective groups often necessitate stringent conditions (such as alkaline hydrolysis of the ester functions). As the use of DTPA bis anhydride may cause excessive unwanted cross-linking, we also developed a procedure by which DTPA mono anhydride is generated in situ as the major reactive DTPA species (see example 4 hereinbelow).

A CA-function can be introduced in a precursor compound of compounds comprising formula 1 at any stage of the synthesis. In some cases it may done at a stage preceding the up join of both ring systems, but often it is more advantageous to introduce the CA-functions at (a) later developmental stage (s), viz. after a joined ring system A and ring system B precursor compound becomes available.

The numerous suitable precursor compounds which enable the synthesis of compounds comprising general formula 1 in their structure, include examplary precursor compounds having a joined ring system A and ring system B precursor as in formulae 20 and 21. However, it will be obvious to one of ordinary skill in the art that numerous ring systems and up joined ring systems have the above-mentioned meanings. Therefore the hereinbelow and hereinfurther described . structures should not be construed as limiting the scope of the present invention but as more specific emodiments of the present invention.

In formulae 20 and 21, A and B denote ring system A and ring system B, respectively; L is in the

meaning of a linking agent (Li), W1, W2, W3, S1, S2, Z3 as well as the integers a, b and c are all as defined hereinabove.

Examplary precursor compounds of formula 20 have an indole skeleton as ring system A and a benzene comprising ring system B. Examplary precursor compounds of formula 21 are formally symmetric with regard the skeletons of ring system A and ring system B, both being represented by a indole. However, due to the occurrence of different substituents and because the lining agent may be assymetric, globally assymetric precursor compounds are also included.

After introduction of suitable CA-functions, and optional modification of W-substituents not involved in the building up of precursor coumpounds can be redrawn as in the following formula 22, representing a more specific embodiment of compounds comprising general formula 1:

whereby the (Li) linking agent L, C1, C2, C3, R1, R2, R3, S1, S2 as well as the numerals n, m, o, q, p and r are as defined and described herein above; affording embodiments that are formally symmetric or assymetric. In a more specific embodiment of formula 22 the linking agent is selected to represent a methylene bridge that is optionally substituted as in formula 23:

wherein R3a and R3b both represent an hydrogen atom or are as desribed hereinbelow As already desribed above precursor compounds of formula 22 having methylene or substituted methylene as linking agent can be obtained by hydroxyalkylation whereby diarylation of aromatic precursor compounds is afforded with aldehydes or ketones. This reaction also enables methylene and substituted methylene bridging of ring systems comprising, for example, indole in their skeleton. In description below we will further explain the present invention with reference to the case of exemplary compounds according to the general formula 1 as embodied in formula 23, in which the linking agent is methylene or substituted methylene and ring system A and ring system B comprise an indole skeleton.

An indole skeleton can be introduced in the molecule (s) making use of for example ethyl-2-indole- carboxylate or indole compounds such as: 5-Chloroindole-2-carboxylic acid, ethyl 5-chloro-2- indolecarboxylate, ethyl 5-fluoro-2-indolecarboxylate, ethyl 5-nitro-and ethyl 7-nitroindole-2- carboxylate, ethyl 5-methoxyindole-2-carboxylate, and numerous other derivatives and/or analogues thereof, which can be purchased or produced according to an overwhelming amount of literature reports dealing with indole-chemistry (see e. g. Organic Synthesis, Cumulative indiches Vol 1-8, 1995 Freeman J. P.; Ed. , J. Wiley & Sons, New York). Indeed, it is known (see e. g as early as Grachner, Mahal & Gerö ; 1923, Helv. Chim. Acta 7: 579-586) that indole derivatives such as ethyl-2-indole-carboxylate can be up linked by reaction with for example formyl-aryl compounds to form 3, 3'arylidenebis (indole-2-carboxylic ethylester) compounds. Hence, easily obtainable formylcompounds such as for example formaldehyde dimethyl acetal, benzaldehyde, methoxybenzaldehyde, formylbenzenesulfonic acid, 4-methoxybenzaldehyde-3-sulfonic acid, carboxybenzaldehyde, tolualdehyde, nitrobenzaldehyde, and those cited above as examples of linking agents of the substituted methylene bridge type (formula 5) are suitable for introducing a a methylene type linking agent.

Examplary embodiments according to formula 24

wherein ring system A and B have both an indole skeleton (S1 and S2 standing here for hydrogen atoms) include various compounds differing with respect to: - the selection and number of R type substituents, each R1 and each R2 substituent may be independently chosen from the list of p-W substituents (for example halogens such as bromo, chloro, fluoro, iodo, functional groups such as nitro and the other W-type substituents including alkoxy and substituents of formula); the selection of the R3a type methylene substituent (R3b standing for hydrogen) whereby the the selection and number of F type substituents may cause variation, the F substituents optionally being selected from the list of ss-W substituents and/or the list of C-functions; the selection of the substituents P-C (=O)-SP1 and ss-C (=O)-SP2, whereby SP1 and SP2 stand for either a CA-function or for a spacer molecule portion bearing a CA function, whereby-SP1 and-SP2 may be identical, partly different or different.

*Precursor compounds enabling synthesis of compounds of formula 24 may bear for example carboxylic esterfunction (such as e. g. 3, 3'-benzylidenebis (indole-2-carboxylic acid ethylester) as primordial ss-C (=O)-SP1 and VC (=O)-SP2 functions. The esters can be for example converted via aminolysis (with e. g. ethylenediamine, piperazine, 2-methylpiperazine and various other diamines, including those cited above under the heading homobifunctional agents: bisamines) and hydrazinolyis (hydrazine) into derivatives which readily react with anhydrides of formula 2 (including for example DTPAmonoethylester monoanhydride) or which react with any kind of insitu activated or preactivated monoreactive bifunctional cheating agent. Accordingly, CA-molecule portions, including those cited in formulae 1 osa to 10g, 11 a and 11 b, can be easily introduced. It is self-evident that prior to conjugation with a CA-precursor, each of the spacers may be further modified, optional modification include for example extension of the spacer.

According to the above it should be obvious that using for example a particular formylcompound not only the-ylidenebis precursor compounds can be synthesized (such as e. g. 3,3' benzylidenebis (indole-2-carboxylic acid ethylester) in which ring A equals ring B, but also for example 3, 3'-benzyliden compounds in which ring A differs from ring B. Assymetric precursor compounds can be produced when for example ethyl-2-indole-carboxylate and one of the above derivatives/analogues are simultaneously brought into reaction with, in this examplary case, benzaldehyde. Such an approach often necesitates separation of the byproducts, viz. the two homo diaryl precursor compounds, from the hetro diaryl precursor compound. Purification may be accomplished according the methods and techniques known to one of ordinary skill in the art, including liquid-liquid extraction, chromatographic procedures, crystalization, selective precipitation.

It should be clear from the above description that a variety of other compounds equally well embody the general formula 1. Moreover excersising the hereinabove desribed procedures, or combinations thereof, enable organic synthesis of a wide variety of specific embodiments of the general formula 1, using a wide variety of precusor compounds which are commercially available or can be produced. Hence, the herein described approach is amenable to produce other compounds, in particular to compunds whereby the R substituents are selected in such a way that a series or a multitude of series of specific compounds, each embodying the structure of general formula 1, are generated which are qualitatively of the same kind but exhibit gradual quantitative differences with respect to blood clearance (ranging from relatively fast to relatively slow), elimination from the body (predominantly by kidney or shifted to more hepatobiliary secretion), plasma protein binding (from low to high).

Homogeneous or heterogeneous labeling of the compounds according to formula 1 can be accomplished by chelation with radioactive or non-radioactive metal ions; preferably with radioactive or non-radioactive ions of an element with atomic number 13,21-32, 37-39,42-44, 49,

50 or 57-83 as for example Mn, Fe, Gd, 99mTc, in,"Ga, Y, 188Re, Re and'Dy.

Chelation with metal ions can be preformed exercising methods amply documented in the literature. Although metal ions can be introduced at any stage of the production (and this may be beneficial in some cases), often it belongs to one of the final steps. When protected functional groups occur in the C-moiety, they may be partly or completely deprotected prior to metal chelation.

Ionizable groups not involved in metal complexation may be optionally neutralized by acidic or basic counter ions or by compounds (inorganic and/or organic) bearing ionizable acidic and/or basic groups Remaining acidic protons, i. e. those that have not been substituted by the metal ion, can optionally be replaced completely or partially by cations of inorganic or organic bases, basic aminoacids or aminoacid amides.

Suitable inorganic counter ions are for example the lithium ion, the potassium ion, the calcium ion, the magnesium ion and especially the sodium ion. Suitable cations of organic bases are, among others, those of primary, secondary or tertiary amines, such as, for example, ethanolamin, diethanolamin, morpholine, glucamin, N, N-dimethylglucamine, tris (hydroxymethyl) aminomethane and especially N-methylglucamine.

Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine as well as the amides of any other acidic or neutral amino acid such as for example lysine methylamide, glycine ethylamide and serine methylamide. A specific embodiment of the present invention was produced by labeling a compound according to the general formula 1 (synthesis is described in examples below) by metal chelation. A representation of a bis Gd 3+ chelate of this species, referred to as EC-V-7, is shown in figure 2.

This example, viz. 3, 3'-bis [indole 2 amide N (11 carboxylat-2 oxo-4,7, 1 0, tris- (carboxylatomethyl) 1,4, 7, 10-tetraundecyl] embodies the general formula 1 in the following way. The nitrogen atom (with H standing for S1) together with the Z1 atoms are represented by the indole skeleton which, in this particular case, is the ring system A devoid of R1 substituents. Ring system B equals ring system A. The linking agent L is available as a phenyl substituted methylene bridge (here devoid of C3). The cheating functions C1 and C2 are identical and are represented by the radical amide N (11 carboxylat-2 oxo-4,7, 10, tris- (carboxylatomethyl) 1,4, 7, 10-tetraundecyl]. In this substituent a DTPA moiety (diethylenediaminepentaacetic acid) provides metal complexing capacity. Remaining acidic protons, i. e. those that have not been substituted by the central metal ion, where neutrilized by the sodium ion.

As will be demonstrated by in vivo results the compound of figure 2, not only embodies the structural features of formula 1, but also enables the other major improvements and qualities of the novel class of compounds. It should be understood that useful compounds exhibiting these merits are not limited to this specific case, the hereinabove cited example is just one example chosen from many other possible examples which could demonstrate the quintessence of the present invention equally well.

Hereinbelow, the present invention is further described and explained by way of examples which are specific embodiments of the present invention and should not be construed as limmiting its scope. The first series of examples will further explain the present invention to the cases of producing compounds embodying formula 1. The second series of examples (bis series) will further explain the present invention to cases (other than synthesis) including for example the use, the in vivo responsiveness and the like topics related to the novel compounds embodying formula 1.

Example 1: DTPA monoethyl monobenzylester Diethylene triamine pentaacetic acid bis anhydride was prepared from DTPA according to the wellestablished pyridine-acetic anhydride method. Two hundred mmol DTPA bis anhydride (71. 4g) and 40mmol dry triethylamine (TEA) in 1100m ! dry DMF were brought into solution (50oC). To the warm solution were added 200mmol absolute ethanol and 200m mol dry benzyl alcohol. After 2 hours solvents were removed under reduced pressure. The DTPA monoethyl monobenzylester was separated from the diethyl ester and the dibenzyl ester by preparative low pressure reversed phase liquid chromatography. Therefor, the residue was dissolved in 250mM phosphate buffer (H3PO4/TEA pH6.5) and applied to a C18 silica column which was developed with an acetonitril gradient. High pressure liquid chromatography (210nm monitoring, Polymer column 4.6/250mm, using a 25mM H3PO4/NaOH pH6. 5-acetonitril gradient, 1 ml/min) showed that pure DTPA monoethyl monobenzylester eluted from the preparative column with 7.5 % acetonitrile/buffer (25mM H3PO4/TEA pH 6.5) to 15% acetonitrile/water. Pure fractions were pooled and concentrated under reduced pressure. Subsequent desalting of the preparation was accomplished by preparative C18 (elution with acetonitrile/water). Solvent from the desalted material was removed under reduced pressure. After removing excess water azeotropically with acetonitril the product was dried in vacuum over P205. Example 2: DTPA mono ethylester DTPA monoethylester was prepared from DTPA monoethyl monobenzylester by hydrogenolysis of the benzylester. The DTPA derivative of example 1 was dissolved in 350 ml 70% (v/v) ethanol/water and 2g palladium on activated carbon (Pd 10%) were added. After a 5 h hydrogen gas (20 PSI) treatment, charcoal was removed by filtration (over a thin path of celte). The retentate was washed with warm 70% (v/v) ethanol/water. Solvents from the combined filtrate and washings were removed under reduced pressure. Drying in vacuum over P205 afforded 27g of DTPA monoethylester. Example 3: DTPA mono ethylester, mono anhydride The product of example 2 was converted to its mono anhydride derivative by the acetic anhydride/pyridine method (250mil acetic anhydride, 42ml pyridine, under nitrogen gas atmosphere). Finally, 14 g (34. 7mmol) of NMR-1H characterized (DMSO D6) DTPA monoethylester monoanhydride was obtained as a white powder. Example 4: DTPA anhydride mono anhydride (in situ generation) For coupling to compounds bearing functional groups (24mmol, such as for example hydrazide, primary, secondary amine), suspend 15. 8g DTPA bis anhydride (44. 3mmol, commercially available or synthesized according to literature reports) in chloroform (200mil), sonicate and collect solid material by filtration, wash with chloroform and finally with pentane. Transfer the amorphous powder to a reaction flask and add 250ml anhydrous DMF, followed by anhydrous triethyl amine (18mi, or another suitable base) to approximate a 3 to 1 ratio. Stir and warm the mixture to 50 OC.

Dissolve 0.94 g water (52mol) in 100mi anhydrous DMF and add the mixture slowly to the warm DTPA bis anhydride solution. Allow the reaction to proceed for 2 hours. Predissolve the compound of interest (24mmol functional groups) in anhydrous DMF (1 00ml or more depending on the solubility) optionally containing H20 (0.22 g 12. 3mmol) and pour the solution in the reaction mixture. Temperature and other parameters influencing the reaction (e. g. total amount of water added, nitrogen gas flushing, etc. ) are controlled as desired.

When the coupling reaction is completed, DMF and triethyl amine are removed under reduced pressure. Often, the final addition of organic solvents, such as for example acetonitril, affords solidification.

Example 5: Precursor compounds of the bis indole type were prepared by coupling indole-compounds having an alkylcarboxylic ester group in a-position. Starting materials were purchased or prepared according to published procedures (see cummulative index Organic Synthesis). The coupling reaction was performed using formaldehyde dimethyl acetal for obtaining 3, 3'methylene- bridged compounds and benzaidehyde (or substituted derivatives thereof) for preparing the 3, 3'benzylidene-bridged compounds. Homodimeric compounds were prepared by reacting a single indole derivative with either formaldehyde dimethyl acetal or a benzaldehyde. Heterodimeric compounds were prepared using either formaldehyde dimethyl acetal or a benzaldehyde reacting and a mixture of two indole derivatives.

Example 6: 3, 3'-benzylidenebis (indole-2-carboxylic acid hydrazide) Five gram (10. 7memo)) 3, 3'-benzylidenebis (indole-2-carboxylic acid ethylester) (see example 5) and 10.73 g hydrazine monohydrate are dissolved in a mixture of 60ml pyridine and 30mi methanol.

After refluxing (80oC) the mixture over night, solvents are removed under reduced pressure. The residue is treated by adding H20, H20/methanol and acetonitril ; after each addition solvent is removed under reduced pressure. Finally, the hydrazide is precipitated from dichloromethan by the addition of acetonitril, the precipitate is collected by filtration and dried over P205 (yield 3.4 gram) Example 7: 3, 3'-benzylidenebis [indole-2-amide N (11-carboxylato-2-oxo-4, 7, 1 0-tris- (carboxylatomethyl)-1, 4,7, 10-tetraundecyl, sodium salt Three gram 3, 3'-benzylidenebis (indole-2-carboxylic acid hydrazide) (6. 85mmol) is dissolved in 200ml dry DMF containing 12ml NN-diisopropylethyl amine. DTPA monoethylester monoanhydride (see example 3) is added (6.6 g, 16. 4mmol) and the mixture is stirred until all starting hydrazide has disappeared. Completion of the reaction is monitored by reversed phase HPLC (gradient elution of a C8/5, column using 25mM TRIS/HCI buffer pH 7.4 containing 0.5mM EDTA and acetonitril). Solvents are removed under reduced pressure. Protective ethylester groups are removed by dissolving the residue in diluted NaOH ; a pH of 13.5 is maintained till all ethylesters are hydrolyzed. After alkaline hydrolysis the pH is adjusted to 7.0 and the sample is applied to a preparative C18 silica column. Low-pressure liquid chromatograph (using a water-methanol gradient) affords the pure ( > 98% by HPLC) title compound. After removal of solvents and drying over P205 a pure white solid is obtained (4.3g). Overall recovery was calculated to approximate 50% when using a FW of 1365 for the following sodium salt C53H56N12020Na8. Example 8: EC-IV-7, viz. the bis gadolinium complex of example 7 Several methods and reagents are available for preparing metalchelates of the new compounds.

For preparing EC-IV-7 gadolinium acetate was incrementally added to an aqueous solution of the compound described under example 11. After each addition the pH was adjusted to 7.4 with NaOH (1. 0M). The formation of mono and bis Gd-chelates was monitored by HPLC (chelation increases the retention time). Addition of Gd-acetate was stopped when the compound was virtually completely converted into the bis and mono gadolinium complex, and the latter amounted to small amounts (total DTPA-moieties not involved in Gd-complexation was less than 10%). A preparation comprising, apart from solutes to make it isotonic to blood, 43mM Gd was used for producing the in vivo MAl-results depicted later on.

Alternatively, formulations optionally comprising additives and/or comprising more or highly concentrated amounts of Gd-compound were prepared from solid product, which was obtained after desalting and drying. Examples of in vivo tests with animals Animal model for liver necrosis : Adult Wistar rats (300-400 g) were anesthetized with intraperitoneal injection of pentobarbital (NembutalO, Sanofi Sante Animale, B-1130 Brussels, Belgium) at a dose of 40 mg/kg. Under laparotomy, reperfused hepatic infarction was induced by temporarily clamping the hilum of the right liver lobe for 3 hours. After reperfusion by decamping hepatic inflow, the abdominal cavity was closed with 2-layer sutures and the rats were left to recover for 8-24 h after the surgery.

MR Imaging : Animals were anesthetized as above for imaging. The tail vein of the rat was cannulated with a G27 infusion set connecting to a 1 ml tuberculin syringe loaded with a solution of the contrast agent. The rat was imaged at 1.5 T (Magnetom Vision, Siemens, Erlangen, Germany) within a homemade cylindrical copper coil [21]. T2-w (TRITE = 3000ms/90ms) and T1-w (TR/TE = 420ms/12ms) spin echo sequences were applied. Other MRI parameters were as follows : slice thickness was 2 mm (without gap); the field of view was 7.5 cm x 10 cm, with a matrix of 192 x 256. Two acquisitions were averaged, resulting in a measurement time of-3 minutes. A glass tube containing 0.02% Cuis04 solution was placed beside the rat as an external standard for normalization of signal intensity (SI) values. Together with a precontrast T1-w imaging, only one T2-w measurement was performed at the beginning to verify the presence of infarcted liver lobe (results not shown). Rats were scanned on transverse sections before and after contrast injection of compound EC-IV-7 at 0.05 mmol Gd/kg. Postcontrast T1-w MRI was taken 5 minutes (early phase), 40 minutes and 24 hours (late phase).

Imaging-histology Correlation : At the end of imaging studies, rats were sacrificed by an intravenous overdose of phenobarbital and placed in a deep freezer (below-20oC) overnight in the same position as that during MR imaging. The frozen rats were sectioned in the transverse plane similar to that on MRI in order to match the imaging and histologic findings. Another approach was to perfuse freshly excercised liver (or other organs) with TTC-solution (2,3, 5-triphenylterazolium) to provoke staining of viable tissue (see literature reports cited in background of the invention). Microscopy Tissue samples were fixated, sectioned, stained and analysed according to standard procedures. Example 1 bis The agent EC-IV-7 ([Gd] of 43mM, with the bis Gd complex as predominant form) was tested in a rat model of reperfused liver infarction. The agent was injected intraveneously at a dose of 50/ymol/kg BW.

Results (see also figure 3) MRI-imaging and post mortem macroscopic analysis show (figures A-E) the blood pool effects and the compound's ability to visualize necrosis.

Indeed, before contrast, the infarcted liver lobe (arrow) is almost isointense relative to the normal liver (A). While immediately after EC-IV-7 injection (B) the signal intensity of normal liver is enhanced, the infarcted lobe (arrow) remains hypointense. All intrahepatic vessels exhibit strong signal intensity, a feature characterizing the reperfused infarction model.

Forty minutes later, the contrast between normal and infarcted liver is reversed due to a combination of events comprising: (1) gradual contrast perfusion and diffusion into the necrotic lobe, (2) declining plasma concentrations (due to slow clearance fom the blood and elimination from the body) and (3) retention of contrast agent in the necrosis by biospecific binding to necrotic tissue or components thereof. The simultaneous occurrence of these dynamic events cause inhomogeneous contrast enhencement of the necrosis at the early phase.

Twenty-four hours after EC-IV-7 administration (D) the signal intensity of both the normal liver and the vessels have largely decreased. However the infarcted lobe displays a persistent homogenous

contrast enhancement, illustrating that EX-IV-7 exhibits necrosis-specificity. Comparison of the in vivo obtained MR-image D with post mortem histologic localisation of necrosis (see E, which shows the necrotic tissue of a rat section corresponding to MAl-slice D), confirms that the observed late phase contrast enhencement exactly matches necrosis. Hence, the newly invented compound has necrosis seeking abilities. In other words it can be used for unambiguous identification and in vivo visualization of necrosis. It was found that blood clearance of the compound was slow (T1/2 of approximately 2.5h). This in conjunction with its ability to reversibly bind to serum proteins, in particular to serum albumin, makes that the compound also exhibits bloodpool effects. Example 2 bis The agent EC-IV-7 (an appropriate dilution, with saline, of a stock preparation of 350mM Gd, with the bis Gd complex as predominant form) was further tested in a rat model of reperfused liver infarction at normal and low dose. One group of annimals received a dose of approximately mol Gd/kg BW while the other received a dose of approximately 10//moi Gd/kg BW.

Results Exciting results were obtained with the low dose because MAl-images an histologic correlation revealed that even at a dose as low as 1 Oijmol Gd/kg BW obvious enhencement of necrotic tissue could be demonstrated. Twentyfour hours post injection of the agent, the observed ratio between normal and necrotic liver was equal or higher than 1. 3. In rats who received the 50, mol Gd/kg BW dose this ratio was greater than 1.6. Taking into account that the agent is cleared rather slowly and that normal liver is involved in eliminating the compound from the body, it is no surprise that after 24h post injection normal liver is still enhancement on MAl images. Consequently, for obvious reasons one may state that in cases where infarction is located in the myocardium and the brain, more generally in organs and/or tissues not involved in elimination of the compound, the contrast ratio will be much higher. Accordingly, doses below 15//moi Gd/kg BW will in vivo effective when the agent is used in systemic applications. In case the site of necrosis permits local administration of the agent (such as for example in case of myocardial infarction: intracoronary) doses far below those effective in systemic applications can be used. Example 3 bis The agent EC-IV-7 ([Gd] of 43mM, with the bis Gd complex as predominant form) was further tested in a rat model of reperfused liver infarction at normal (approximately 50/7mol Gd/kg BW) and low dose (approximately 15, mol Gd/kg BW). The agent was administered after a delay of 48 hours following inducing the liver infarction.

Results MAl-images an histologic correlation revealed that when the compound was administered even after 48h post trauma excelent enhancement of necrosis was obtained, i. e. the observed contrast ratios were similar as in the previous experiment. Example 4 bis Possible toxic side effects of the agent EC-V-7 (stock solution of 350mM Gd, with the bis Gd complex as predominant form) were studied in normal Wistar rats (n=5) that received a bolus injection (intra veneous) of approximately 1000 mol Gd/kg BW. After treatment the animals were kept in standard laboratory cadges, and had free acces to water and food. The behaviour of the rats was carfully monitored during the first 10h post injection. After 24h the animals were sacrificed, organs were excercised and macroscopically inspected. Tissue samples were collected and prepared for microscopic analysis.

Results None of the rats showed any abnormal behaviour after receiving the high dose of agent EC-V-7.

Post mortem inspection of organs did not reveal any abnormalities. Extensive microscopic analysis of tissue samples (liver, heart, kidney, brain and muscle) did not show any abnormal histology and did not reveal any histological indication of toxicity (such as e. g. inflamation, necrosis, and the like) Accordingly, it is concluded that the agent is essentially non-toxic and well-tolerated.

Claims (1)

1. What is claimed is: 1. Compounds of the following general formula

   wherein - L represents a direct link or an optionally substituted linking agent (Li), which links a ring system A with a ring system B by covalent bonding; - the ring system A comprises Z1, which represents the atoms necessary to complete a substituted or unsubstituted unsaturated or partially saturated monocyclic or polycyclic carbocyclic or heterocyclic ring system around the S1 substituted nitrogen atom; - the ring system B comprises Z2, which represents the atoms necessary to complete a substituted or unsubstituted unsaturated, partially saturated or aromatic monocyclic or polycyclic carbocyclic or heterocyclic ring system around the X atom. the X atom being a carbon atom or a S2 substituted nitrogen atom; - the substituents S1 and S2 are independently from each other a hydrogen atom or a saturated or partially unsaturated alkyl, aryl or aralkyl chain optionally having one or more heteroatoms and optionally substituted by functional groups or atoms; - L is a direct bond or an optionally substituted linking agent Li; - R1, R2 and R3 are optional substituents (R) of the ring system A, the ring system B and the linking agent, respectively. The indices q, p and r are integers indicating the number of R substituents present on the Z1 skeleton, the Z2 skeleton and the linking agent Li, respectively and Cl, C2 and C3 are optional substituents (C) of the ring system A, the ring system B and the linking agent, respectively, which make metal complexation obtainable. The indices n, m and o are integers indicating the number of R-substituents present on the Z1 skeleton, the Z2 skeleton and the linking agent Li, respectively. 2. Compounds of claim1 in which L means a direct link.

   3. Compounds of claim1 in which L means a linking agent (Li), whereby Li is in the meaning of: - a straight chain or branched-chain, saturated, partly saturated or partly aromatic group designated as organylene, organohetryl-organyl or organohetrylene ; - a bridging heteroatom, wherein heteroatom is oxygen (-0-) or sulfur (-S-) ; - a bridging functional group not having carbon, said the aminyl of formulae-NH-, N-substituted aminyl derivatives of formula-N (Rxn) -, the hydrazo of formulae-NH-NH-or the N-substituted or the N, N'-substituted derivatives, the sulphonohydrazide of formula-S (=0) 2--NH-NH-, the sulphonamide of formula-S (=0) 2-NH- or the sulphonyl group of formula-S (=0) 2- ; - a bridging functional group having carbon, selected from the group consisting of acyl having formulae-C (=O)- or-C (=N-Rxn) -, ester of formula-C (=O)-O-, aldimine of formula-N=CH-, ketimine of formula-N=C (Rxk) -, urethane of formula-N (Rxu) -C (=O)-O-, carbonhydrazide of formula-C (=O)-NH-NH-, N-, N'-or N, N'-substituted carbonhydrazide, sulphonohydrazide of formula-S (=0) 2-NH-NH-, N-, N'-or N, N'-substituted sulphonohydrazide, bisacyl hydrazide of formula-C (=O)-NH-NH-C (=O)-, N-, N'-or N, N'-substituted bisacyl hydrazide, amide of formula -C (=O)-NH-, N-substiuted amide, secondary amide of formulae-C (=O)-NH-C (=O)- or -C (=O)-N (-C (=O)-Rxa)-, sulfonamide of formula-S (=0) 2-NH- and N-substituted sulfonamide. 4. Compounds of any of the claims 1 to 3, wherein each of the optional R1-substituents, each of the optional R2-substituents and each of the optional R3-substituents is independently selected from the organyl or organohetryl radicals of formula

   p-W whereby - the bond ss refers to the bond through which the substituent is attached and W is a substituent independently selected from the list consisting of: halogens, organyl groups, organyloxy groups, organylaza groups, organylthio groups, functional groups, the oxo radical (=O) and the thio radical (=S).

   5. Compounds of claim 4 wherein ss-W is selected from the group consisting of: the hydroxyl (-OH), the oxo (=O), the allyl (-CH2-CH=CH2), the vinyl (-CH=CH2), the thiol (-SH), the thio (=S), the thiocyanato (-SCN), the nitryl (-N02), the nitrosyl (-NO), the aminyl (-NH2), the iminyl (=NH), the hydrazinyl (-NH-NH2), the azidyl (-N3), the carboxyl (-C02H), the sulphono (-S03H), the phosphono (-P (=O) (OH) 2), the cyanyl (-CN), the sulfamino (-NHS03H), the allophanoyl (-C (=O)-NH-C (=O)-NH2), the guanyl (-C (=NH) -NH2), the acetyl (-C (=O)-CH3), the carboxyl (-COOH), the carboxamide (-C (=O)-NH2), the carboxamidine (-C (=NH) -NH2), the formyl (-C (=O)-H), the formamidyl (-NH-C (=O)-H) and the phosphonooxy group (-O-P (=O) (OH) 2).

   6. Compounds of any claims 1 to 5, wherein each of the the optional d-substituents, each of the optional C2-substituents and each of the optional C3-substituents is independently selected from the organyl and organohetryl substituents of formula P- (K-8) 0-,-CA wherein - indicates the bond to the joined ring system A and ring system B and 8 indicates the bond of K to molecule portion CA; - K is an optional bivalent chain of formula p-K-8, whereby the K stands for a molecule portion identical to Li as described in claim 3; - CA is a cheating agent, said CA is either directly (ss-CA) or via a bivalent chain O-K-8 connected as substituent, having the meaning of organyl or an organohetryl group having in its substructure: - one or more thiol bearing moieties, one or more bisamine-bisthiol, one or more bisamine bisoxime, one or more monomercapto-triamide, one or more diamide-dithiol, one or more monoamine-monoamide-dithiol, one or more tetramine, one or more monoamine-diamide monothiol, one or more monoamine-monothioether-dithiol, one or more monoamine-monothiol,

   one or more monoamide-diamine-monothiol and/or one or more diphosphine moieties ; and/or - one or more structural elements of one of the following formulae

   wherein Z'is selected from the group consisting of phosphonomethyl (-CH2PO3HRz), carboxy methyl (-CH2COORz), substituted carboxy methyl (-C (Zx) HCOORz), carboxy ethyl (-CH2CH2COORz), substituted carboxy ethyl of formulae-C (Zx) HCH2COORz and - CH2C (Zy) HCOORz), and wherein Z"is selected from the group consisting of hydrogen, phosphonomethyl (-CH2PO3HRz), carboxy methyl (-CH2COORz), substituted carboxymethyl (-C (Zx) HCOORz), carboxy ethyl (-CH2CH2COORz), substituted carboxy ethyl of formulae-C (Zx) HCH2COORz and - CH2C (Zy) HCOORz, hydroxyethyl (-CH2CH2ORz), substituted hydroxyethyl of formulae

   - C (Zx) HCH2ORz and-CH2C (Zy) HOH ; 7. Compounds according to claim 6, said compounds having a CA molecule portion of formula

   or of formula

   wherein the index a stands for the numerals 0 to 6 at least one carbon or one hetero atom is involved in covalent ss or 8 bonding at the hereinbelow cited locations ; each V independently of one another for an, optionally substitute, saturated, partly unsaturated, aromatic or partly aromatic organylene group, said V may stand for optionally substituted phenylen, optionally substituted diphenylen or for an optionally substituted C2-C30 straight chain or branched-chain hydrocarbylene group wherein the chain or parts of the chain optionally can form a cyclic C5-C8 unit or a bicyclic C10-C14 unit; optionally the hydrocarbylene group contains phenylen (-C6H4-), oxygen (-0-), sulfur (-S-), aminyl (-NH-), N-substituted aminyl of formula-NRxn-or-N (-Z) -, aminyl as part of the aforementioned cyclic units (-N (-)-), aminyl involved in ss or 8 bonding carbonyl (-C (=O)-), thiocarbonyl (-C (=S) -) ; the hydrocarbylene group can be optionally substituted by halogens, functional groups and/or by lower (hetero) alkyl, (hetero) aryl and/or (hetero) aralkyl groups that are optionally substituted by halogens and/or by functional groups and/or by optionally by halogens and/or by functional groups substitute radicals of formulae

   - (CH2) o. 5- (C6H4) o.,- (O) o-,- (CH2) o-s- (C6H4) o-,- (O) o-,-M and/or - (CH2) o-5- (C6H10) o-1- (0) 0. 1- (CH2) o. 5- (C6H4) o-1- (0) 0-1-M wherein the molecule portion M stands for hydrogen, Rz, Q or a-CH2CH2-Q group with Q, Z and Rz as described hereinbelow ; each aminyl Z-substituent can stand independently of one another for hydrogen, for the organyl groups of formulae - CH (Zx)- [- (CH (Zy)-] o-1-Q and -C (=O)-CH (Zx) -Q wherein the molecule portion Q stands for a direct bond (p or 8) or a bonding group having -C (=O)-P/ 8 or-NH-0/8, phosphono (-POsH2) or derivatives thereof (-P03HRz), carboxy (-COOH) or derivatives thereof (-COORz), amide (-C (=O)-NH2) or derivatives thereof (-C (=0)-NH-Rzd1 and-C (=O)-N (-Rzd2)-Rzd1), hydrazide (-C (=0)-NH-NH-Rzh1 and - C (=0)-NH-N (-Rzh2)-Rzh1), hydroxy (-OH) and derivatives (-ORz), thiol (-SH) and derivatives (-SRz), a small saturated, partly saturated or aromatic 5 or 6 membered heterocyclic organyl or organohetryl group comprising one or more heteroatoms and optionally substituted by 1 to 3 substituents independently selected from the the group consisting of functional groups and lower alkyl groups; wherein Zx and Zy are independently selected from the group consiting of a direct bond (ss or 8) or a bonding group comprising-C (=O)- or -NH- involved in ss or 8 bonding, hydrogen, carboxy (-COORz), a straight or branched 2-alkenylgroup or derivatives thereof involved in ss or 8 bonding, the lower alkyl, aryl and aralkyl group that is optionally substituted by halogens and/or by functional groups and optionally contains one or more heteroatom (s) and the optionally by halogens and/or by functional groups substituted radicals

   - (CH2) 0-5- (C6H4) 0. 1- (O) o-i- (CH2) 0-5- (C6H4) 0-1- (O) O-,-M and - (CH2) o-5- (C6H10) o-1- (0) 0-1- (CH2) o. 5- (C6H4) 0. 1- (0) o. i-M wherein the molecule portion M stands for hydrogen, Rz, a-CH2CH2COORz group, a direct ss or 8-bond or a bonding group involved in ss or 8 bonding containing-C (=O)- and/or -NH-, a small saturated, partly saturated or aromatic 5 or 6 membered heterocyclic organyl or organohetryl group that contains one or more heteroatoms, that is optionally substituted by 1-3 substituents independently selected from the group consisting of functional groups and lower alkyl groups; with Rzh1, Rzh2, Rzd1, Rzd2 in the meaning of substituents and each Rz may be independently selected from the group consisting of hydrogen, straight chain or branched chain saturated or parly unsaturated alkyl-, aralkyl-or aryl-groups that are optionally substituted by halogens and/or by functional groups and that optionally contain one or more heteroatoms, bonds involved in metal complexation and an organic or inorganic cation. 8. Compounds according to claim 7 wherein CA is selected from as a derivative of the compounds of the group consisting of: mercaptoacetyl tripeptides, mercaptoacetyl triglycine (MAG3), a propylene diamine dioxime tetraligand bearing one or more alkyl substituents, hexamethyl propylene diamine dioxime (HMPAO), ethylene dicysteine, ethylene cysteine cysteamine, cysteinylglycine cysteine, bismercaptoacetyldiaminopropionic acid, bismercaptoacetyidiaminosuccinic acid, N- (mercaptoacetylaminoethyl)-cysteine, dimercaptosuccinic acid, dimercaptopropionic acid, cysteine, cysteamine and diphosphinopropionic acid, or of the group consisting of ethylenediaminetetraacetic acid, diethylene triaminopentaacetic acid, triethylene tetramine

   hexaacetic acid, trans-1, 2-cyclohexanediamine tetraacetic acid, 1, 4, 7, 1 0-tetraazacyclododecane tetraaceticacid, 1, 4, 7-triazacyclononanetriacetic acid, 1, 4, 8, 11-tetraazatetradecanetetraacetic acid, 1,5, 9-triazacyclododecanetriacetic acid, and analogues of the aforementioned in which one or more carboxy methyl groups are replaced by hydrogen or by another aminyl Z-substituent so that Z as defined in claim 7 together with the aminyl group (referred to as amino) to which it is attached represents: : aminoethanol, 2-amino-2-ethyl-1, 3-propandiol, 3-methyl-1-butamine,

   6-amino-2methyl-2-heptanol, 2- (2-aminoethoxy) ethanol, 1- (3-aminopropyl) imidazole, 4- (3-aminopropyl) morpholine, 1- (3-aminopropyl)-2-pipecoline, 1- (3-aminopropyl)-2-pyrrolidinone, 1- (2-aminoethyl) pyrrolidine, 1- (2-aminoethyl) pyrrolidine, 1- (2-aminoethyl) piperidine, 2- (2-aminoethyl) pyridine, 2- (aminomethyl) pyridine, 1- (2-aminoethyl) pyrrolidine, 4- (2-aminoethyl) morpholine, 4- (2-aminoethyl)-1-methylpyrrolidine, (aminomethyl) cyclopropane, 2- (aminomethyl) pyridine, 3- (aminomethyl) pyridine, 2- (aminomethyl)-1-ethylpyrrolidine, furfurylamine, tetrahydrofurfurylamine, 2- (aminomethyl)-tetrahydropyran,

   2- (aminomethyl)-1, 3-dioxolane, 2- (aminomethyl)-1-methylimidazole, N- (2-aminoethyl) piperidine, N- (2-aminoethyl) morpholine, 3- (2-aminoethyl) indole, natural occuring aminoacids (D, L and DL) and analogues thereof, 9. Compounds according to claim 6 wherein CA comprises one of the following structures:

   whereby the arrows indicates the bonding position, and Rz is as defined in claim 7.

   10. Compounds according to any of the claims 1 to 9, the compounds labeled by one or more dense and/or one or more ratioactive atoms; 11. Compounds according to any of the claims 1 to 10, the compounds being labeled by homogeneous or heterogeneous metal chelation with one or more radioactive or non-radioactive metal ions; preferably selected from the list comprising radioactive or non-radioactive ions of an element with atomic number 13,21-32, 37-39,42-44, 49,50 or 57-83 such as for example Mn, Fe,

   67 186 163 Gd, 99mTc,"lln, Ga, 90Y, 18BRe, Re and Dy.

   12. A pharmaceutically acceptable salt of a compound as claimed in any of the claims 1 to 11 13. A pharmaceutical composition comprising a compound as claimed in any of the claims 1 to 11 or a combination thereof and a pharmaceutically acceptable carrier or excipient together with it.

   14. A compound or a pharmaceutical composition thereof according to any of the claims 1 to 13, for use in diagnosis or therapy of a disease in a subject.

   15. The compound or a pharmaceutical composition thereof according to any of the claims 1 to 14, for imaging in a subject.

   16. The compound or a pharmaceutical composition thereof according to any of the claims 1 to 14, for magnetic resonance imaging or nuclear scintigraphy imaging in a subject.

   17. The compound or a pharmaceutical composition thereof according to any of the claims 1 to 16, wherine said compound is spurious necrosis specific.

   18. The compound or a pharmaceutical composition thereof according to any of the claims 1 to 16, wherein said compound is a truely necrosis avid agent.

   19. The compound or a pharmaceutical composition thereof according to any of the claims 1 to 16 for use as a multipurpose contrast agent of the human or non-human animal body.

   20. The compound of any of the claims 1 to 19, which does not cause histological abnormalities in a subject which received an intravenous bolus of a bis gadolinium complex of said compound of 500 to 1000 pmol/kg body weight.

   21. The use of the compound or the pharmaceutical composition thereof as claimed in any of the claims 1 to 14 in the manufacturing of a medicament for diagnosis or therapy of disease in a subject.

   22. The use of the compound or the pharmaceutical composition thereof as claimed in any of the claims 1 to 14 in the manufacturing of a medicament for genarating of an image of at least part of the body of a subject.

   23. The use of the compound or the pharmaceutical composition thereof as claimed in any of the claims 1 to 14 in the manufacturing of a multipurpose contrast agent of the human or non-human animal body.

   24. The use of the compound or the pharmaceutical composition thereof as claimed in any of the claims 1 to 14 in the manufacturing of a medicament for imaging in a subject, wherin a bis gadolinium complex of said compound is used systemically as a contrast agent at a dose lower than 60pmol/kg body weight.

   25. The use of the compound or the pharmaceutical composition thereof as claimed in any of the claims 1 to 14 in the manufacturing of a medicament for imaging in a subject, wherin a bis gadolinium complex of said compound is used systemically as contrast agent at a dose ranging from 10 to 20 mol gadolinium/kg body weight.

   26. The use of the compound or the pharmaceutical composition thereof as claimed in any of the claims 1 to 20 for imaging in a subject.

   27. The use of the compound or the pharmaceutical composition thereof as claimed in any of the claims 1 to 20 for imaging in a subject, wherby said imaging is a magnetic resonance imaging or a nuclear scintigraphy imaging.

   28. The use of the compound or the pharmaceutical composition thereof as claimed in any of the claims 1 to 20 for visualising, identifying, differentiating or localising organs, parts of organs, tissues or systems of the group consisting of vasculatory systems, hepatobiliary systems and renal-urinary systems.

   29. A method for visualising, identifying, differntiating or localising necrosis of a subject, wherein compounds of any of the claims 1 to 20 or a pharmaceutically acceptable composition thereof is is administered to said subject.

   30. The method of claim 29 wherein said visualising or differentiating of necrosis is aided by magnetic resonance imaging or nuclear scintigraphy imaging.

   31. The method of claims 29 or 30, wherein the necrosis is caused by a pathological condition.

   32. The method of any of the claims 29 to 31, wherein the necrosis is caused by a therapeutic condition.

   33. The method of any of the claims 29 to 32, wherein the necrosis is caused by a myocardial infaction or a cerebral infarction.

   34. The method of any of the claims 29 to 33 for diagnosing necrosis, comprising administering to a patient suffering from or suspectibe to said necrosis an effective amount of said compound.