GB2453654A

GB2453654A - A compound for use in X-ray contrast examinations

Info

Publication number: GB2453654A
Application number: GB0818398A
Authority: GB
Inventors: Duncan George Wynn
Original assignee: GE Healthcare AS
Current assignee: GE Healthcare AS
Priority date: 2007-10-12
Filing date: 2008-10-08
Publication date: 2009-04-15
Also published as: GB0818398D0

Abstract

The compound of formula (I) may be used as a diagnostic agent for X-ray contrast examinations.

Description

1 2453654 Title: Contrast Agents

Technical Field of the Invention

The present invention relates to a compound and to diagnostic compositions containing the compound where the compound is an iodine containing compound. More specifically the iodine containing compound is chemical compound containing two linked iodinated phenyl groups.

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 lsovuelM), iomeprol (marketed e.g. under the trade name lomeronTM) and the non-ionic dimer iodixanol (marketed under the trade name and Visipaque').

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 iodiriated 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 g 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 dirners 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.

In patients with acute renal failure, nephropathy induced by contrast medium remains one of the most clinically important complications of the use of iodinated contrast medium. Aspelin, P et al, The New England Journal of Medicine, Vol 348:491-499 (2003) concluded that nephropathy induced by contrast medium may be less likely to develop in high risk patients when iodixanol is used rather than a low-osmolar, non-ionic contrast medium.

The part of the patient population considered as high risk patients is increasing. To meet the need for continuous improvement of in vivo X-ray diagnostic agents for the entire patient population, there is a continuous drive in finding X-ray contrast agents that has improved properties, also with regards to contrast induced nephrotoxicity (CIN).

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 VisipaqueTM at the desired osmolality (WO 90/01194 and WO 91/1 3636).

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 media containing a chemical compound as the active pharmaceutical ingredient(s) having two triiodinated phenyl groups linked by a linking group are usually referred to at dimeric contrast agents or dimers. During the years a wide variety of iodinated dimers have been proposed. Relevant patent publications comprises EP 1186305, EP 686046, EP108638, EP 0049745, EP 0023992, WO 2003080554, W02000026179, WO 1997000240, Wa 9208691, US3804892, US4239747, US3763226, US3763227 and US3678152. At this time, one contrast medium having a iodinated non-ionic dimer as the active pharmaceutical ingredient is one the market the product VisipaqueTM containing the compound iodixanol. The compound HexabrixTM, containing the ionic dimeric compound ioxaglic acid is also on the market.

W092/08691 of Dibra and Bracco proposes symmetrical or asymmetrical I,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-( mono-or poly-hydroxyalkyl)aminocarboriyl-2,4,6-triiodo-benzoyl-amino}-hydroxy or hydroxyalkyl-propanes and exemplifies a number of these compounds. Tables 1 and 2 provide some test results of the compounds of Examples 1 and of the patent specification. However, none of the compounds prepared in W092/08691 are developed and brought to the market.

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 and any additional adverse effect known or discovered for such iodinated compounds

Summary of the Invention

The present invention provides a chemical compound useful as contrast media having desired properties with regards to at least one of the criteria mentioned above and in particular to renal toxicity, osmolality, viscosity and solubility. The contrast media comprises the iodine containing contrast enhancing compound where the iodine containing compound is a chemical compound containing two linked iodinated phenyl groups. The iodine containing contrast enhancing compound can be synthesized from commercially available and relatively inexpensive starting materials.

Detailed Description of the Invention

The new compound of the invention, its use as X-ray contrast agent, its formulation and production are specified in the attached claims and in the specification hereinafter The contrast enhancing compound is a synthetic chemical compound of formula (I)

HO NOH

OH OH OH

0 I 0 0 I 0 Formula (I) and salts or optical active isomers thereof.

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 0.42 M (Molar). The contrast medium will also be hypo-osmolar 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 The compound of formula (I) also comprises optical active isomers and may exist in several isomer-ic forms due to chiral carbon atoms. In addition, the compounds exhibit exo/endo isomerism due to the restricted rotation of the amide bond caused by the proximity of the bulk iodine atom Both enantiomerically pure products as well as mixtures of optical isomers are included.

The compound 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 the 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 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 mOsmfkg H20.

With the compound of the invention such viscosity, osmolality and iodine concentrations targets can be met. Indeed, effective iodine concentrations can be reached with hypotoriic 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 WO 90/01194 and WO 91/1 3636.

In particujar, 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.

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.

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.

Hence, the invention further embraces use of a diagnostic agent and a diagnostic composition containing the compound of formula (I) in X-ray contrast examinations and use of the 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 the compound of formula (I) to the human or animal body, examining the body with a diagnostic device and compiling data from the examination is also provided In the method of diagnosis the body may also be preadministrated with the compound 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 data from the examination and optionally analysing the data In the method of imaging the body may also be preadministered with the compound of formula (I) The compound of formula (I) can be synthesized by a multistep procedure as shown below from starting materials that are either known from the state of art or that are commercially available or can readily be produced from commercially available materials

NH NH NH NO

I i I I I I I I 0 HO -OH HO.-OH Ci..-Ci Cl I o o a i o o o O i: V,VI OH° kk.-i OH 0 OH 0 OH HOOH Cl)LLOH 0 I 0 0 I 0 0 I 0 (I) H2S04, Formaldehyde, 50°C; (ii) SOd2, DMF, 70°C, (iii) CH2(OH)COCI, DMAc, (iv) 3-methylamino-1,2,-propanediol, NEt3, DMAc; (v), 1,3-diamino-2-propanol, NEt3, DMAc; (vi) NH3, MeOH Preparations A to E illustrate the synthesis of the intermediates used in the procedure above.

Preparation A 2,4,6-Trliodo-5-methylamino-jsophthapic acid

HN

HO OH 0 I 0

5-Amino-2,4,6-triiodoisophthalic acid (50g, 89.5mol), readily available from Aldrich, was dissolved slowly in concentrated sulphuric acid (200m1) at 50°C. The resulting purple solution was then added dropwise to formaldehyde (38% by weight, lOOmI) maintaining a temperature of between 50-50°C. The solution was stirred for 2 hours at 50°C and then allowed to cool. The mixture was poured onto ice water (3L) and the solid was collected by filtration and dried in a vacuum oven at 50°C for 7days to give 2,4,6-triiododo-5-methylamino-isophthalic acid (55.3g).

Mass Spec (ESI) mlz: [M+H]4 = 574.36.

13C NMR (DMSO; 300MHz) 6 169.84, 152 75, 149 44, 90 49, 80.00, 35.55 Preparation B 2,4,6-Triiodo-5-methylamino-jsophthaloyl dichloride

HN lJ,,l Cl Cl 0 I 0

2,4,6-Triiododo-5-methylamino-iscphthal,c acid (50g, 87.3mmol) was stirred in thionyl chloride (275ml, 1.4lmol) and DMF (imi) at 70°C for 72 hours. The thionyl chloride was removed under reduced pressure and the resulting solid was partitioned between ethyl acetate (400m1) and ice water (200m1). The organic layer was collected, dried over MgSO4, filtered and evaporated to dryness The product was purified by silica column chromatography eluting with petrol ethyl acetate to give 2,4,6-Triiodo-5-methylamino-isophthaloyl dichloride (30.93g. 50. 7mmol).

13C NMR (DMSO, 300MHz) 6 169 42, 154 03, 149 85, 89.82, 7523, 3558.

Preparation C Acetic acid [(3,5-bis-chlorocarbonyl-2,4,6-triiodophenyl)methylcarbamoylj.methyl ester Cl If 0 I 0 2,4,6-Triiodo-5-methylamino-isophthajoyl dichioride (20g, 32.8mmol) was dissolved in DMA (60m1) and acetoxyacetyl chloride (15.32m1, l42mmol) was added The reaction was stirred overnight at room temperature with nitrogen bubbling through the reaction mixture. The reaction mixture was poured slowly onto ice-water (300m1) and a white solid was isolated by filtration The solid was dissolved in ethyl acetate and washed with water. The ethyl acetate was collected, dried over MgSO4, filtered and evaporated to give a white solid. This was purified by silica column chromatography eluting with petrol: ethyl acetate to give acetic acid [(3S-bis-chlorocarbonyl.2,4,6triiodophenyl)methylcarbamoyp]methyl ester (16.25g, 22.9mmol).

Mass Spec (ESI) m/z [M+HJ = 710.73.

1H NMR (CDCI3; 300MHz) ö = 4.32 (s, 2H), 3.26 (s, 3H), 2.13 (s, 3H) 13C NMR (COd3; 300MHz) 6 = 170.11, 165.19, 151 89, 147.88, 9591,8421,6239,34 17, 20.47.

Preparation 0 Acetic acid ({3-chlorocarbonyj.54(2,3-djhydroxypropyI)..methyJ..carbamoyI12,4, 6-triiodo-phenyl}-methyl-carbamoyl)-rnethyj ester HOJ1IXLcl Acetic acid [(3, 5-bis-chlorocarbonyl-2,4, 6-triiodo-phenyl)-methyl-ca rbamoyl]- methyl ester (16.25g, 22.9mmol) and 3-methylamino-1,2,-propanediol (4.42ml, 45.8mmol) were stirred in DMA (80ml) for 72 hours at room temperature. The mixture was diluted with ethyl acetate (150m1) and washed with ice water! brine (50:50, 20m1 x3). The organics were collected, dried over MgSO4, filtered and evaporated to dryness. The product was purified by silica column chromatography eluting with DCM: methanol to give acetic acid ({3-chlorocarbonyl-5- [(2, 3-dihydroxy-propyl)-methyl-carbamoyI]-2,4,6-triiodo-phenyI} methyl-carbamoyl)-methyI ester (5.42g, 6.96mmol).

Mass Spec (ES I) m/z: [M+H} = 778 72 Preparation E N-(2, 3-Dihyd roxy-propyl)-N'-(3-{3-F(2, 3-d ihydroxy-propyl)-5-[(2-acetoxy-acetyl)-methyl-ami no methyl-carbamoyl]-2,4,6-trjjodo-benzoylamino}-2-hydroxypropyl)-5-[ (2-acetoxy-acetyl)-methyl-aminol-2,4,6-triiodo-N-methyl-isophthalamide

I OH OH

0 I 0 0 I 0 Acetic acid ({3-chlorocarbonyl-5-[(2,3-dihyd roxy-propyl)-methyl-carbamoyl]-2,4,6-triiodo-phenyl}-methyl-carbamoyl) -methyl ester (2.4g, 3.O8mmol) was dissolved in dry DMA (8m1) and triethylamine (429.it, 3.O8mmol) and 1,3-diamino-2-propanol (111mg, 1.23mmol). The reaction was stirred for 5 days at room temperature. The reaction mixture was diluted with DCM (3Oml) and washed with water (lOmI). The aqueous layer was collected, and evaporated to dryness. It was purified by column chromatography eluting with DCM: Methanol to give the desired product (1.29g, 0.823mmo1) Mass Spec (ESI) m/z: [M+HJ = 1574.68.

The final product was prepared according to Example 1:

Example 1

N-(2, 3-Dihydroxy-propyl)-N'-(3-{3-f (2, 3-dihyd roxy-propyl)-5-U2-hydroxy-acetyi)-methyl-amino methvJcarbamoyl1246triiodobenzoyIamIflo}2hydr0xypropyI)51(2hydroxyacetl) methyl.amino]2,4,6..trijodo..N..methyI..,sQphthalamide

HO NOH

OH OH OH

0 I 0 0 I 0 N(23Dihydroxypropyl)..N'..(3{3..[(23dihydroxyprQpyl)5[(2acetoxyacetyI) methyla.

methyl-ca rbamoyi].2,4,6-triiodobenzoylamino}2.hydroxy..propyl)-5-[ (2-acetoxy-acetyl)-methyl-amino]-2,4,6trlpodoN..methyli5ophthaIamide (1.29g, O.823mmo1) was stirred in ammonia in methanol (4m1, 7N) for 24h at room temperature. The solvent was removed under reduced pressure and the final product was purified by preparative HPLC to give N- (2, 3-Dihydroxy-propyl)-N -(3-{3-[(2,3-d ihyd roxy-propyl)-5-[(2-hycJroxyacetyp)-methyl-amino-methYl-carbamoyI}2, 46triiodobenzoyIamIflo}2.hydroxypropyI)S[(2hyd roxy-acetyl)-methyl-amino]-2,4,6-trliodo-N-methyl-isophthajamjde (637mg, O.427mmo1) as a white solid.

Mass Spec (ESI) m/z: [M+H] = 1490.62.

Claims

Claims 1 Compound of formula (I)

HO NOH

OH OH OH

0 I 0 0 I 0 Formula (I) and salts or optical active isomers thereof.
2. A diagnostic agent comprising the compound of formula (I) of claim 1
3. A diagnostic composition comprising the compound of formula (I) of claim 1 together with a pharmaceutically acceptable carriers or excipients
4. An X-ray diagnostic composition comprising a compound of formula (I) of claim 1 together with a pharmaceutically acceptable carriers or excipients.
5. Use of a diagnostic agent and a diagnostic composition containing a compound of formula (I) of claim 1 in X-ray contrast examinations.
6. Use of a compound of formula (I) of claim 1 for the manufacture of a diagnostic composition for use as an X-ray contrast agent.
7 A method of diagnosis comprising administration of the compound of formula (I) of claim 1 to the human or animal body, examining the body with a diagnostic device and compiling data from the examination.
8. A method of diagnosis comprising examining a body preadministered with the compound of formula (I) of claim iwith a diagnostic device and compiling data from the examination. 0 13
9. A method of Imaging, specifically X-ray imaging, comprising administration of the compound of formula (I) of claim 1 to the human or animal body, examining the body with a diagnostic device and compiling data from the examination and optionally analysing the data.