GB2457358A - X-Ray contrast agents comprising three iodinated phenyl groups - Google Patents

Abstract

Compounds of formula below, where each R denotes a triiodophenyl group optionally further substituted, and each R3 denotes a hydrogen or a C1-C4 alkyl group optionally substituted by hydroxyl or amino groups and optionally interrupted by an oxygen atom. R are preferably 2,4,6-triodophenyl groups optionally further substituted at the 3 and/or 5 positions by non-ionic hydrophilic moieties R4, such as di- or trihydroxyalkylaminocarbonyl moieties. Compounds exemplified have R3 = H or CH3, and two identical R4 = CONHCH2CHOHCH2OH or CON(CH2CH2OH)2. These compounds, where three iodinated phenyl groups are arranged around a central methane core containing amide functions, are contrast agents useful in diagnostic compositions and contrast media for X-Ray imaging. Use in diagnostic and imaging methods is also outlined.

Description

Title: Contrast Agents

Technical Field of the Invention

The present invention relates to a class of compounds and to diagnostic compositions containing such compounds where the compounds are iodine containing compounds More specifically the iodine containing compounds are chemical compounds containing a central moiety containing amide functions allowing for the arrangement of three iodinated phenyl groups bound thereto.

The invention also relates to the use of such diagnostic compositions as contrast agents in diagnostic imaging and in particular in X-ray imaging and to contrast media containing such compounds

Description of Related art

All diagnostic imaging is based on the achievement of different signal levels from different structures within the body. Thus in X-ray imaging for example, for a given body structure to be visible in the image, the X-ray attenuation by that structure must differ from that of the surrounding tissues. The difference in signal between the body structure and its surroundings is frequently termed contrast and much effort has been devoted to means of enhancing contrast in diagnostic imaging since the greater the contrast between a body structure and its surroundings the higher the quality of the images and the greater their value to the physician performing the diagnosis. Moreover, the greater the contrast the smaller the body structures that may be visualized in the imaging procedures, i.e. increased contrast can lead to increased spatial resolution.

The diagnostic quality of images is strongly dependent on the inherent noise level in the imaging procedure, and the ratio of the contrast level to the noise level can thus be seen to represent an effective diagnostic quality factor for diagnostic images.

Achieving improvement in such a diagnostic quality factor has long been and still remains an important goal. In techniques such as X-ray, magnetic resonance imaging (MRI) and ultrasound, one approach to improving the diagnostic quality factor has been to introduce contrast enhancing materials formulated as contrast media into the body region being imaged.

Thus in X-ray early examples of contrast agents were insoluble inorganic barium salts which enhanced X-ray attenuation in the body zones into which they distributed. For the last 50 years the field of X-ray contrast agents has been dominated by soluble iodine containing compounds. Commercial available contrast media containing iodinated contrast agents are'usually classified as ionic monomers such as diatrizoate (marketed e.g. under the trade name GastrografenTM), ionic dimers such as ioxaglate (marketed e.g. under the trade name HexabrixTM), nonionic monomers such as iohexol (marketed e.g. under the trade name OmnipaqueTM), iopamidol (marketed e.g under the trade name IsovueTM), iomeprol (marketed e.g. under the trade name lomeronTM) and the non-ionic dimer iodixanol (marketed under the trade name and VisipaqueTM).

The most widely used commercial non-ionic X-ray contrast agents such as those mentioned above are considered safe Contrast media containing iodinated contrast agents are used in more that 20 millions of X-ray examinations annually in the USA and the number of adverse reactions is considered acceptable. However, since a contrast enhanced X-ray examination will require up to about 200 ml contrast media administered in a total dose, there is a continuous drive to provide improved contrast media.

The utility of the contrast media is governed largely by its toxicity, by its diagnostic efficacy, by adverse effects it may have on the subject to which the contrast medium is administered, and by the ease of storage and ease of administration. Since such media are conventionally used for diagnostic purposes rather than to achieve direct therapeutic effect, it is generally desirable to provide media having as little as possible effect on the various biological mechanisms of the cells or the body as this will lead to lower toxicity and lower adverse clinical effect. The toxicity and adverse biological effects of a contrast medium are contributed to by the components of the formulation medium, e.g. the solvent or carrier as well as the contrast agent itself and its components such as ions for the ionic contrast agents and also by its metabolites.

The major contributing factors to the toxicity of the contrast medium are identified as the chemotoxicity of the contrast agent, the osmolality of the contrast medium and the ionic composition or lack thereof of the contrast medium Desirable characteristics of an iodinated contrast agent are low toxicity of the compound itself (chemotoxicity), low viscosity of the contrast medium wherein the compound is dissolved, low osmolality of the contrast medium and a high iodine content (frequently measured in mg iodine per ml of the formulated contrast medium for administration). The iodinated contrast agent must also be completely soluble in the formulation medium, usually an aqueous medium, and remain in solution during storage.

The osmolalities of the commercial products and in particular of the non-ionic compounds is acceptable for most media containing dimers and non-ionic monomers although there is still room for improvement. In coronary angiography for example, injection into the circulatory system of a bolus dose of contrast medium has caused severe side effects. In this procedure contrast medium rather than blood flows through the system for a short period of time, and differences in the chemical and physiochemical nature of the contrast medium and the blood that it replaces can cause undesirable adverse effects such as arrhythmias, QT prolongation and reduction in cardiac contractive force. Such effects are seen in particular with ionic contrast agents where osmotoxic effects are associated with hypertonicity of the injected contrast medium. Contrast media that are isotonic or slightly hypotonic with the body fluids are particularly desired. Low osmolar contrast media have low renal toxicity which is particularly desirable. The osmolality is a function of the number of particles per volume unit of the formulated contrast medium.

To keep the injection volume of the contrast media as low as possible it is highly desirable to formulate contrast media with high concentration of iodine/mI, and still maintain the osmolality of the media at a low level, preferably below or close to isotonicity. The development of non-ionic monomeric contrast agents and in particular non-ionic bis(triiodophenyl) dimers such as iodixanol (EP patent 108638) has provided contrast media with reduced osmotoxicity allowing contrast effective iodine concentration to be achieved with hypotonic solution, and has even allowed correction of ionic imbalance by inclusion of plasma ions while still maintaining the contrast medium VisipaquelM at the desired osmolality (WO 90/01194 and WO 91/13636).

The X-ray contrast media at commercial high iodine concentration have relative high viscosity, ranging from about 15 to about 60 mPas at ambient temperature. Generally, contrast media where the contrast enhancing agent is a dimer has higher viscosity than the corresponding contrast media where the contrast enhancing agent is the monomer corresponding to the dimer Such high viscosities may pose problems to the administrators of the contrast medium, requiring relatively large bore needles or high applied pressure, and are particularly pronounced in pediatric radiography and in radiographic techniques which require rapid bolus administration, e g in angiography.

X-ray contrast agents of high molecular weight has been proposed, e.g. polymers with substituted triiodinated phenyl groups grafted on the polymer, see EP 354836, EP 436316 and US 5019370. Further, WO 9501966, EP 782563 and US patent 5817873 read on compounds having e.g 3 and 4 substituted triiodinated phenyl groups arranged linearly or around a central core. However, none of these proposed compounds are on the market.

Hence there still exists a desire to develop contrast agents that solves one or more of the problems discussed above. Such agents should ideally have improved properties over the soluble iodine containing compounds on the market in one or more of the following properties: renal toxicity, osmolality, viscosity, solubility, injection volumes/iodine concentration and attenuation/radiation dose.

Summary of the Invention

The present invention provides compounds useful as contrast media having improved properties over the known media with regards to at least one of the following criteria osmolality (and hence the renal toxicity), viscosity, iodine concentration and solubility. The contrast media comprises iodine containing contrast enhancing compounds where iodine containing compounds are chemical compounds containing a central compact moiety, allowing for the arrangement of three iodinated phenyf groups bound to thereto through linker groups containing amide functions. The iodine containing contrast enhancing compounds can be synthesized from commercially available and relatively inexpensive starting materials.

Detailed Description of the Invention

The new compounds of the invention, their use as X-ray contrast agents, their formulation and production are specified in the attached claims and in the

specification hereinafter.

The contrast enhancing compounds are synthetic chemical compounds of formula (I) R1R1 Formula (I) and salts or optical active isomers thereof wherein each R1 independently are the same or different and denote a moiety -CO-NR3-R; R2 denotes a hydrogen atom, hydroxyl group or a C1-C4 alkyl group where the alkyl group may be substituted by hydroxyl and amino groups and interrupted by an oxygen atom; each R3 independently are the same or different and denote a hydrogen atom, hydroxyl group or a C1-C4 alkyl group where the alkyl group may be substituted by hydroxyl and amino groups and interrupted by an oxygen atom; each R independently are the same or different and denote a trilodinated phenyl group, preferably a 2,4,6-triiodinated phenyl group further substituted by two groups R4 wherein each R4 are the same or different and denote a hydrogen atom or a non-ionic hydrophilic moiety, provided that at least one R4 group in the compound of formula (I) is a hydrophilic moiety.

The substituents R1 above are the same or different. Preferably R3 denotes a hydrogen atom or a methyl group. When R3 denotes a hydrogen atom then R1 denotes the moiety -CO-NH-R. It is further preferred that the substituent R2 denotes a hydrogen atom or a methyl moiety, most preferably R2 denotes a hydrogen atom.

Each of the iodinated R groups can be the same or different and preferably denote a 2,4,6-triiodinated phenyl group, further substituted by two groups R4 in the remaining 3 and 5 positions in the phenyl moiety Preferably all three R groups in the compound of formula (I) are the same, and even more preferred each substituent R have two hydrophilic moieties which may be the same or different.

The non-ionic hydrophilic moieties may be any of the non-ionizing groups conventionally used to enhance water solubility Hence, the R4 substituents may be the same or different and shall preferably all denote a non-ionic hydrophilic moiety comprising esters, amides and amine moieties, optionally further substituted by a straight chain or branched chain C110 alkyl groups, preferably C15alkyl groups, where the alkyl groups also may have one or more CH2 or CH moieties replaced by oxygen or nitrogen atoms. The R4 substituents may also further contain one or more groups selected from oxo, hydroxyl, amino or carboxyl derivative, and oxo substituted sulphur and phosphorus atoms. Each of the straight or branched alkyl groups preferably contains I to 6 hydroxy groups and more preferably 1 to 3 hydroxy groups.

Therefore, in a further preferred aspect, the R4 substituents are the same or different and are mono or polyhydroxy C15a1ky1, hydroxyalkoxyalkyl with ito carbon atoms and hydroxypolyalkoxyalkyl with 1 to 5 carbon atoms, and are attached to the iodinated phenyl group via an amide or a carbamoyl linkage, preferably amide linkages.

The R4 groups of the formulas listed below are particularly preferred: -CONH-CH2-CH2-OH -CONH-CH2-CHOH-CH2-OH -CON(CH3)CH2-CHOH-CH2QH -CONH-CH-(CH2 -OH)2 -CON-(CH2-CH2-OH)2 -CONH2 -CONHCH3 -CONH-CH2-CH2-O-CH3 -CONH-O-CH3 -CONH-CH2-CHOH-CH2-O-CH3 -CONH-CH2-CHOCH3-CH2-OH -CON (CH2-CHOH-CH2-OH) (CH2-CH2-OH) S 7 -CONH-C (CH2 -OH)2 CH3 -CONH-C (CH2 -OH)3 -CONH-CH (CH2-OH) (CHOH -CH2-OH) -CON-(CH2-CHOH-CH2-OH)2 -NHCOCH2OH -N(COCH3)H -N(COCH3) C13 alkyl -N(COCH3) -mono, bis or tris-hydroxy C14 alkyl -N(COCH2OH) -hydrogen, mono, bis or tris-hydroxy C14 alkyl -N(CO-CHOH-CH2OH) -hydrogen, mono, bis or trihydroxylated C1 alkyl.

-N(CO-CHOH-CHOH-CH2OH) -hydrogen, mono, bis or trihydroxylated C,4 alkyl -N(CO-CH-(CH2OH)2) -hydrogen, mono, bis or trihydroxylated C14 alkyl, and -N(COCH2OH)2 Even more preferably the R4 groups will be equal or different and denote one or more moieties of the formulas -CONH-CH2-CHOH-CH2-OH, - CON(CH3)CH2-CHOH-CH2OH, -CONH-CH-(CH2 -OH)2 -CON-(CH2-CH2-OH)2, -CON-(CH2-CHQH-CH2-OH)2 -CONH-CH2-CHOH-CH2-OH, and even more preferably all R groups are the same and the R4 groups in each R are the same or different and denote -CONH-CH2-CHQH-CH2-OH or CON(CH3)CH2-CHOH-CH2OH. Particularly preferably all the R4 groups are the same and denote -CONH-CH2-CHQH-CH2-QH.

Most preferably all substituents R1 in formula (I) are equal.

Thus, the most preferred structures according to the invention include the compounds of formula (II): CH (CO-NH-R)3 Formula (II) In formula (II), each group R has the meaning above, more preferably each iodophenyl groups R are the same and the R4 groups all denote non-ionic hydrophilic moieties as noted above.

A preferred example the structure according to the invention includes the compounds of formulas (lila) to (Ilif) below.

OH OH

H I

HO ON-1....OH OH HO 0 N..}....OH OH

HO H

O N}..OH I 0 NOH HO NH 0 HNNH 0 o HO HN o J NH 0 HO HNO I N. HO (OH HO1 (OH

OH

OH

O I NH 0 I N..

OH

OH OH

HO OH OH OH

H

HO 0 OH HO ONOH OH HO 0 N 0H HO 0 N OH HN..1(L..(LN 0 HOJ0 0 OH 0 i HO HNO NOH HO N o I NH (OH HOX

OH

HO'1 N..}....,0H 0 i NH OH 0H OH

OH

OH

OH (OH

OH

HO 0 N -LOH OH 0 N HO OH ON) HO1 0 N N RIINH o N 0 (OHo I O1'N HO NO I N HN'1O N

HO

HO' 1OH HO,N (OFLOH

OH

0 I N 0 I N)

OH OH

OH

Formulas (lila) to (Ilif)

S

The compounds of formula (I) will attain a relatively compact, folded conformation. Such conformations are relatively round and globular forms such as a star-form with the relatively bulky iodinated phenyl substituents filling up the area between the 3 arms of the star. When the central trimeric core is a tricarbonyimethane group as in the compound of formula (lila) above, then the calculated diameter taken as an average of the distance between the extreme hydrogen atom in the R4 groups and the central carbon atom is approximately 12.3 Angstrom, which indicate that the compounds are compact, globular molecules.

At an iodine concentration of 320 mg/mI, which is a common concentration for commercially available iodinated contrast media, the concentration of the compound of formula (I) will be approximately 0.28 M (Molar). The contrast medium will also be hypoosmolar at this iodine concentration, and this is an advantageous property with regards to the nephrotoxicity of the contrast medium. It is also possible to add electrolytes to the contrast medium to lower the cardiovascular effects as explained in WO 90/01194 and WO 91/1 3636.

Compounds of formula (I) also comprises optical active isomers. Both enantiomerically pure products as well as mixtures of optical isomers are included.

The compounds of the invention may be used as contrast agents and may be formulated with conventional carriers and excipients to produce diagnostic contrast media.

Thus viewed from a further aspect the invention provides a diagnostic composition comprising a compound of formula (I) as described above together with at least one physiologically tolerable carrier or excipient, e.g in aqueous solution for injection optionally together with added plasma ions or dissolved oxygen.

The contrast agent composition of the invention may be in a ready to use concentration or may be a concentrate form for dilution prior to administration.

Generally compositions in a ready to use form will have iodine concentrations of at least 100 mg i/mi, preferably at least 150 mg I/mi, with concentrations of at least 300 mg I/mi, e.g. 320 mg I/mi being preferred. The higher the iodine concentration, the higher is the diagnostic value in the form of X-ray attenuation of the contrast media. However, the higher the iodine concentration the higher is the viscosity and the osmolality of the composition.

Normally the maximum iodine concentration for a given contrast media will be determined by the solubility of the contrast enhancing agent, e g. the iodinated compound, and the tolerable limits for viscosity and osmolality.

For contrast media which are administered by injection or infusion, the desired upper limit for the solution's viscosity at ambient temperature (20°C) is about 30 mPas, however viscosities of up to 50 to 60 mPas and even more than 60 mPas can be tolerated For contrast media given by bolus injection, e.g. in angiographic procedures, osmotoxic effects must be considered and preferably the osmolality should be below 1 Osm/kg H20, preferably below 850 mOsm/kg H20 and more preferably about 300 mOsm/kg H20.

With the compounds of the invention such viscosity, osmolality and iodine concentrations targets can be met. Indeed, effective iodine concentrations can be reached with hypotonic solutions. It may thus be desirable to make up the solution's tonicity by the addition of plasma cations so as to reduce the toxicity contribution that derives from the imbalance effects following bolus injection. Such cations will desirably be included in the ranges suggested in In particular, addition of sodium and calcium ions to provide a contrast medium isotonic with blood for all iodine concentrations is desirable and obtainable. The plasma cations may be provided in the form of salts with physiologically tolerable counterions, e.g. chloride, sulphate, phosphate, hydrogen carbonate etc., with plasma anions preferably being used.

In a further embodiment the invention provides diagnostic agents comprising a compound of formula (I) and diagnostic compositions comprising a compound of formula (I) together with pharmaceutically acceptable carriers or excipients. The diagnostic agents and composition are preferably for use in X-ray diagnosis.

The contrast media containing compounds of formula (I) can be administered by injection or infusion, e.g. by intervascular administration. Alternatively, contrast media containing compounds of formula (I) may also be administered orally. For oral administration the contrast medium may be in the form of a capsule, tablet or as liquid solution.

Hence, the invention further embraces use of a diagnostic agent and a diagnostic composition containing a compound of formula (I) in X-ray contrast I 11 examinations and use of a compound of formula (I) for the manufacture of a diagnostic composition for use as an X-ray contrast agent.

A method of diagnosis comprising administration of compounds of formula (I) to the human or animal body, examining the body with a diagnostic device and compiling data and images from the examination is also provided. In the method of diagnosis the body may also be preadministrated with compounds of formula (I).

Furthermore, a method of imaging, specifically X-ray imaging is provided, which comprises administration of compounds of formula (I) to the human or animal body, examining the body with a diagnostic device and compiling images and data from the examination and optionally analysing the images and data. In the method of imaging the body may also be preadministrated with compounds of formula (I).

Preparation The compounds of the general formula (I) can be synthesized by multistep procedures from starting materials that are either known from the state of art or that are commercially available. Tri-iodinated phenyl groups R and precursors thereof are commercially available or can be produced following procedures described or referred to e.g. in W095/35122 and W098/52911. 5-amino-2,4,6-tri,odo -isophtalic acid for example is available e.g. from Aldrich and 5-amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)jsophtalamide is commercially available e.g. from Fuji Chemical Industries, Ltd. The central tricarbonylmethane starting material for reaction with precursors of the R group where the group R has a free amino function and where the hydroxy functions of the R4 group are protected, e.g. by acylation, preferably acetylation, are readily synthesized from commercially available triacids of formula CR2(COOH)3, e.g. by the formation of a acid chloride following the procedure of Preparation A below.

The reactive acid groups, e.g. as their acid chlorides, are then reacted with the precursor or the R-group having a free amino function, and if necessary, hydrolysis of R4 protected groups such as esters using traditional deacetylation methods to produce the compound of formula (I) as visualised

in Example 1 below

The final product is then purified by conventional methods such as semi-preparative HPLC Preparation of methanetricarbonyjch(or-jde HOOC COOH (COd)2 coc coc

Y Y

COOH coci Methane tricarboxylic acid (7 4 g, 50 mmol) is treated with oxalyl chloride (20 ml) and dry N,N-dimethylformamide (1 drop) under an atmosphere of nitrogen.

The mixture is heated at refiux until all the solid is dissolved, the excess oxalyl chloride is evaporated and the isolated tricarbonyl chloride is dried in vacuo and used without further purification.

The preparation of the acetylated triiodophenyl-amino isophtalamide intermediates are prepared following the synthesis described by K M R Pillai, G Diamantidis, L Duncan and R S Ranganathan, J Org Chem, 1994, 59 (6), 1344.

The acetylated intermediate compounds are finally deacetylated following state of art procedures to yield compounds of formula (I).

Example 1:

Tris(3'5'-N-di(N-2",3"-dihydroxypropyaminocarbonyl)..246..

triiodophenyl)methanecarboxamjde A) Preparation of tns(3'5'-N-di(N-2",3"-ciiacetoxypropylaminocarbonyl)246.

triiodophenyl)methanecarboxamjde o J,OAc OAc 0 N,0AC

HN

cioc coci 0 1'

I NH

coo HN 0 Tricarbonyl chlonde (0.2 g, 1 mmol) and N,N'-di(2,3-diactoxypropyl) 5-amino- 2,4,6-triiodoisophthalamjde (4.5 g, 5 mmol) are dissolved in dry N,N-dimethylacetamide (30 ml). The mixture is stirred at room temperature for 3 days with nitrogen bubbling through the reaction mixture. The mixture is diluted with ethyl acetate (100 ml) washed with ice-water (5 x 50 ml), dried over magnesium sulphate, filtered and evaporated. The resulting solid is purified by chromatography using ethyl acetate:dichloromethane.

B) Preparation of tns(3'5'-N-di(N2",3"djhydroxypropyIaminocarboflyf)246..

triiodophenyl)methanecarboxam,de OAc i-f Oc OH

_HOIOH

o I NH O'f"N I,I HO1 HN 0 -j.. 0 OAc HO OH o: The dodecaacetate (1 g, 0 4 mmol) is dissolved in methanol (20 ml) and treated with 0.880 ammonia (1 mi) The mixture is stirred for 2 hours. The solvent is removed in vacuo and the resulting solid is purified by HPLC Following the procedure of Example 1, compounds of formula (IlIb), (Ilic), (hId), (tile), ((ill) are prepared.

Claims (4)

1. Claims 1 Compounds of formula (I) R1<R1 Formula (I) and salts or optical active isomers thereof wherein each R' independently are the same or different and denote a moiety -CO-NR3-R; R2 denote a hydrogen atom, hydroxyl group or a C1-C4 alkyl group where the alkyl group may be substituted by hydroxyl and amino groups and interrupted by an oxygen atom; each R3 independently are the same or different and denote a hydrogen atom, hydroxyl group or a C1-C4 alkyl group where the alkyl group may be substituted by hydroxyl and amino groups and interrupted by an oxygen atom; each R independently are the same or different and denote a triiodinated phenyl group, preferably a 2,4,6-triiodinated phenyl group further substituted by two groups R4 wherein each R4 are the same or different and denote a hydrogen atom or a non-ionic hydrophilic moiety, provided that at least one R4 group in the compound of formula (I) is a hydrophilic moiety.
2. 2. Compound as claimed in claim 1 wherein R2 and R3 independently denote hydrogen atoms or methyl groups.
3. 3. Compound as claimed in claim 2 wherein each R2 and R3denote hydrogen atoms.
4. 4. Compound as claimed in any of the preceding claims wherein each R are the same or different and denote a 2,4,6 triiodinated phenyl group, further substituted by two groups R4 wherein each R4 are the same or different and denote a non-ionic hydrophilic moiety compnsing esters, amides and amine moieties, optionally further substituted by a straight chain or branched chain C1.10 alkyl groups preferably C15 alkyl groups, optionally with one or more CH2 or CH moieties replaced by oxygen or nitrogen atoms and optionally substituted by one or more groups selected from oxo, hydroxyl, amino or carboxyl derivative, and oxo substituted sulphur and phosphorus atoms Compounds as claimed in claim 4 wherein R4 are the same or different and denote a non-ionic hydrophilic moiety comprising esters, amides and amine moieties, further substituted by a straight chain or branched chain C1.5 alkyl groups substituted by ito 6, preferably ito 3 hydroxy groups.6. Compounds as claimed in claim 5 wherein each R4 are the same or different and are mono or polyhydroxy C15alkyl, hydroxyalkoxyalkyl with 1 to 5 carbon atoms and hydroxypolyalkoxyalkyl with 1 to 5 carbon atoms attached to the iodinated phenyl group via a amide linkages.7. Compounds as claimed in any of the preceding claims wherein each R4 are the same or different and are selected from groups of the formulas -CONH-CH2-CH2-Ql-J -CONH-CH2-CHOH-CH2-OH -CON(CH3)Cl-12-CHQH-CH2QH -CONH-CH-(CH2 -OH)2 -CON-(CH2-CH2-OH)2 -CONH2 -CONHCH3 -CONH-CH2-CH2-Q-CH3 -CONH-O-CH3 -CONH-CH2-CHOH-CH2-O-CH3 -CONH-CH2-CHOCH3-cH2-QH -CON (CH2-CHOH-CH2-OH) (CH2-CH2-OH) -CONH-C (CH2 -OH)2 OH3 -CONH-C (CH2 -OH)3 -CONH-CH (CH2-OH) (CHOH -CH2-OH) -CON-(CH2-CHQH-0H2-QI-1)2 -NHCOCH2OH I.'' 17 -N(COCH3)H -N(COCH3) C1.3 alkyl -N(COCH3) -mono, bis or tris-hydroxy C14 alkyl -N(COCH2OH) -hydrogen, mono, bis or tris-hydroxy C14 alkyl -N(CO-CHOH-CH2OH) -hydrogen, mono, bis or trihydroxylated C1 alkyl -N(CO-CHOH-CHOH-CH2OH) -hydrogen, mono, bis or trihydroxylated C14 alkyl -N(CO-CH-(CH2OH)2) -hydrogen, mono, bis or trihydroxylated C14 alkyl, and -N(COCH2OH)2 8 Compounds as claimed in claim 7 wherein each R4 are the same or different and are selected from groups of the formulas -CONH-CH2-CHOH- CH2-OH, -CON(CH3)CH2-CHOH-CH2OH, -CONH-CH-(CH2 -OH)2 -CON- (CH2-CH2-OH)2, -CON-(CH2-CHOH-CH2-OH)2 and -CONH-CH2-CHOH-CH2-OH, 9. Compounds as claimed in any of the preceding claims wherein all R4 entites are the same.10. Compounds as claimed in claim 1 of formula (II) CH (CO-NH-R)3 Formula (II) wherein each R preferably are the same and the R4 groups all denote non-ionic hydrophilic moieties.11. Compound of claim 10 being tris(3'5'-N-di(N-2",3"-dihydroxypropylaminocarbonyI).2,4,6_tr,jodophenyl) methanecarboxamide 12 A diagnostic agent comprising a compound of formula (I) as defined in any of the preceding claimsI-13 A diagnostic composition comprising a compound of formula (I) as defined in any of the preceding claims together with a pharmaceutically acceptable carriers or excipients.14 An X-ray diagnostic composition comprising a compound of formula (I) as defined in any of the preceding claims together with a pharmaceutically acceptable carriers or excipients.Use of a diagnostic agent and a diagnostic composition containing a compound of formula (I) as defined in any of the preceding claims in X-ray contrast examinations.16 Use of a compound of formula (I) as defined in any of the preceding claims for the manufacture of a diagnostic composition for use as an X-ray contrast agent.17. A method of diagnosis comprising administration of compounds of formula (I) as defined in any of the preceding claims to the human or animal body, examining the body with a diagnostic device and compiling images and data from the examination.18. A method of diagnosis comprising examining a body preadministered with compounds of formula (I) as defined in any of the preceding claims with a diagnostic device and compiling images and data from the examination.19. A method of imaging, specifically X-ray imaging, comprising administration of compounds of formula (I) as defined in any of the preceding claims to the human or animal body, examining the body with a diagnostic device and compiling data from the examination and optionally analysing the data.