CA2215385A1 - X-ray contrast media for computer tomography and urography - Google Patents
X-ray contrast media for computer tomography and urography Download PDFInfo
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- CA2215385A1 CA2215385A1 CA002215385A CA2215385A CA2215385A1 CA 2215385 A1 CA2215385 A1 CA 2215385A1 CA 002215385 A CA002215385 A CA 002215385A CA 2215385 A CA2215385 A CA 2215385A CA 2215385 A1 CA2215385 A1 CA 2215385A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
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Abstract
A radiographic contrasting agent having the formula (I) based on triiodinated isophthalic acid amide is disclosed, as well as its use and a process for preparing the same. In the formula, R1 stands for the methyl residue and R2 for the 2,3-dihydroxypropyl residue or R1 and R2 stand each for a 2-hydroxyethyl residue.
Description
CA 0221~38~ 1997-09-1~
X-Ray Contrast Media for Computer Tomography and Urography The invention relates to the object characterized in the claims, i.e., new iodine-containing x-ray contrast media, their production and uses. The new compounds solve important problems in contrast-enhanced computer tomography. Further, they are very well suited for urography.
Contrast media are indispensable for medical diagnostic radiology. Many radiological studies cannot yield useful information without contrast media. Urography, visualization of the blood vessels and cardiac ventricles, the subarachnoid spaces, the lymph tracts, and the gastrointestinal tract, and numerous pathological processes in computer tomography can be mentioned.
The first intravascularly injectable, relatively universally usable iodized x-ray contrast media were produced more than 50 years ago. These products, originally salts of mono-iodized organic acids, have since been improved in many ways as regards their effectiveness and compatibility. The best contrast media now available carry 3 or 6 iodine atoms per molecule instead of originally a single iodine atom; they are no longer salts, but rather neutral, sugar-like substances, and the osmolality of their solutions is, in the most advantageous case, no longer tenfold or more higher than that of blood; rather, it is blood-isotonic despite extremely high concentrations.
CA 0221~38~ 1997-09-1~
The compatibility of the new contrast media seemed at first to fulfill all wishes simultaneously. Thus, the same products were used for very different applications, such as intravenous injection, arteriography, venography, cardiography, myelography, the visualization of the gastrointestinal tract, and many other body cavities. Only the contrast medium concentration in the solution and the injected or infused volumes were adapted to the special test. A well-known product was dubbed Omnipaque(R) to reflect this concept, i.e., it was supposed to be suitable for all indications.
In contrast, especially in the last 10 years, there has been further development of individual contrast medium-enhanced x-ray methods, with increasingly more specific requirements imposed on the contrast media used in each case. Vasography is performed not only for diagnostic purposes, but at the same time is being used more and more often as a less-invasive means of access to therapeutic interventions for pathological changes in the body that are otherwise only surgically accessible. For example, as part of angiographic tests with visualization of the blood vessels by catheters through which the contrast media are injected, simultaneously and with the same catheters, stenoses of the coronary arteries can be dissolved, and blood vessels supplying tumors can be enlarged without the chest having to be opened up surgically. Clots can be dissolved by specific selective infusion of thrombolytic agents into the affected blood vessels, blood vessels supplying tumors can be sealed by selective injection of microparticles or certain embolisates that CA 0221~38~ 1997-09-1~
consolidate in the blood, or internal bleeding can be controlled with the last-mentioned process or vascular anomalies in the brain can be treated. In this connection, contrast media are injected first for diagnostic purposes and then very often repeated to monitor the treatment process in certain vascular regions (interventional radiology). Since these procedures are performed in most cases in older, seriously ill patients, extreme requirements with respect to vascular compatibility and --because of the total dose being cumulative -- also with respect to general compatibility are to be imposed on the contrast media.
However, other requirements are less critical: the modern image-processing techniques make it possible, in most cases, to operate with lower contrast medium concentrations, so that the desired low viscosity of the solutions is now easier to achieve.
Further, it is known that nausea and vomiting, as well as allergy-like reactions occur more rarely after arterial administration of contrast media by catheter than after intravenous injection by needle. In this regard as well, the contrast media for vascular diagnosis with the aid of a catheter are therefore not to be judged as critically as intravenously injectable products.
At this time, certainly, the so-called nonionic dimeric (hexaiodized) contrast media, which are distinguished particularly by excellent vascular compatibility, are to be evaluated as optimum for most arterial and direct venous vasographies.
CA 0221~38~ 1997-09-1~
There are similar special requirements, for example, on contrast media for the visualization of other body regions. Very good neural compatibility is indispensable for the visualization of the vertebral canal (myelography). The contrast medium should also exhibit high enough viscosity that dilution by bodily fluids is carried out as slowly as possible. The same requirement for slow dilution is imposed in the visualization of joint cavities.
In diagnostic radiology of the gastrointestinal tract, it is a requirement that the contrast medium exhibit an acceptable taste, be diluted slightly by osmosis, and not trigger any diarrhea. In past years, however, the above-mentioned processes have become less important since there are now other diagnostic methods with which satisfactory results are achieved in many cases.
Computer tomography is of extraordinary importance that is even increasing even more due to recent technical developments.
Unlike in other x-ray techniques, it is not an area (for example, the chest) that is irradiated, but only a disk a few millimeters thick, for example, through the skull or body, and this disk is calculated and presented as a sectional image. While computer tomography originally required about 20 seconds to obtain the data for such a disk, this process is completed in 1 second or 50 milliseconds in modern devices. At the same time, the patient can be moved through the measuring device, so that, for example, in 30 seconds, 30 layers in 5 mm layer thickness are covered and thus a body section that is 15 cm in length.
After intravenous injection, the usual contrast media can reveal the blood vessels and show the perfusion of vessels, CA 0221~38~ 1997-09-1~
organs and tissues, as well as the permeability of capillaries by overflow from the blood space into the considerably larger intercellular space of the tissue.
Many pathological changes can be detected especially well during the first passage of the contrast medium after quick intravenous injection since the distribution differences in the healthy tissue are the most pronounced at that point. It is clear that quick computer tomographs, which cover entire body sections within a few seconds or display the timing of the contrast medium's passage through a certain region by fast repeated images, can reveal these contrast medium distribution differences best of all. Quick computer tomography has therefore become an increasingly more important and increasingly more widely used tool of medical diagnosis. Approximately half the amounts of x-ray contrast media now used are employed in computer tomography.
The method of application and the requirements imposed on contrast media in computer tomography differ significantly from those for catheter arteriography and venography. To achieve sufficient contrast, large amounts of contrast media must be quickly injected intravenously through comparatively narrow cannulae. Amounts of contrast media corresponding to 15-45 g of iodine per single injection are necessary. It may be necessary -- or it is even usual - to repeat the individual injections at intervals of a few minutes. In the case of efficient quick computer tomographs, the injection rate is generally 1-5 ml/sec or more (Small, W. C.; Nelson, R. C.; Bernadino, M. E.; Brummer, L. T.: Contrast-Enhanced Spiral CT of the Liver: Effects of Different Amounts and Injection Rates of Contrast Material on Early Contrast Enhancement. AJR 163, 87-92, 1994).
To be able to inject these amounts quickly, the contrast medium solutions must be sufficiently thin at high iodine concentration. The contrast medium side effects that are most common and most disruptive after intravenous administration (Dawson, P.; Clau~, W., Edts: Contrast Media in Practice, Springer Verlag Berlin Heidelberg 1993, pp. 107-109), such as nausea, vomiting and allergy-like reactions, should occur as seldom as possible. Extremely high dosages must be tolerated by all organs despite corresponding previous injury in many patients.
It should be possible to produce the contrast media at reasonable cost so as to not unnecessarily restrict the availability of the relatively economical computer tomographic examination methods per se. Since intravenous injection only rarely results in irritation of the local veins or after dilution in the heart, or even irritation of the arteries, no extreme requirements are imposed on the local vascular compatibility of the contrast media for computer tomography. Contact with the central nervous system is possible only after at least 10-fold dilution by the general blood circulation, so that neural compatibility should be completely satisfactory for almost all intravascular contrast media.
Requirements similar to those of computer tomography are also to be imposed on contrast media for elimination urography.
CA 0221~38~ 1997-09-1~
Also, these contrast media are quickly administered intravenously. The specific diseases of the patients for whom urography is to be performed, as well as the need for high-contrast and complete radiological visualization of the urinary passages, impose additional requirements on compatibility, elimination, and diuretic effects.
Many of the now available water-soluble x-ray contrast media and the new developments in recent years attempt to meet the requirements of widely varying classes of applications simultaneously, while others are specially tailored to the angiographic application. Some exhibit widely varied deficiencies and are optimally suitable for none of the above-mentioned applications. The substances (iopentol, iohexol, ioversol) contain, for example, a relatively small iodine content, which results in elevated viscosity of their solutions.
Simultaneously, osmolality rises to an undesirable extent.
Nonionic dimeric contrast media (iotrolan, iodixanol) are desirably blood-isotonic, but simultaneously also viscous. New contrast media with very high iodine content (for example, the compounds mentioned in Patent Specifications US 5047228 and US
5019371) seem to combine low osmolality and viscosity in an ideal way. Inadequate water-solubility and problems of compatibility, however, have thus far prevented successful development.
The group of contrast media thus far best suited to the requirements of computer tomography consists of chemically very closely related compounds: iopromide, iopamidol, and iomeprol.
They are distinguished by low viscosity (for fast injection) with CA 0221~38~ 1997-09-1~
low osmolality (for low cardiovascular system stress) and acceptable general and organ compatibility. Thus, they come closest to meeting the requirements of contrast media that can be injected intravenously quickly and in high doses.
The steady development of computer tomography and the repeated study of very seriously ill patients require, however, further improvement, especially of the compatibility of the x-ray contrast media provided for this application, without the iodine content being reduced as in the other mentioned substances and thus viscosity being increased and injectability deteriorating.
The object of the invention is thus to make available such compounds and tools, as well as to provide a process for their production. The achievement of this object is done by the objects characterized in the claims.
It has been found that two new compounds show surprisingly advantageous properties, especially when used in computer tomography. In this case, these are compounds of general formula I
IR' O~N'R2 ~ ~ NH ~ OH
(I) in which either CA 0221~38~ 1997-09-1~
-R1 stands for the methyl radical and R2 stands for the 2,3-dihydroxypropyl radical or -R1 and R2 in each case stand for the 2-hydroxyethyl radical.
While the osmolality, viscosity, and iodine content are very similar to those of the structural isomeric compounds iopamidol and iomeprol, a surprisingly high hydrophilia of the compounds according to the invention can be seen (Tab. 1).
Tab. 1: Butanol/water (buffer pH 7) -- distribution coefficient of different contrast media, n = 4, average value + standard deviation and iodine content of the molecule Distribution Iodine Content (%) Coefficient Example 1 0.069 + 0.011 49 Iopromide - 0.149 + 0.011 4%
Iopamidol 0.089 + 0.014 49 Iomeprol 0.105 + 0.006 49 Iohexol 0.082 + 0.005 46 The substance according to Example 1 exhibits the smallest distribution coefficient of the structurally comparable CA 0221~38~ 1997-09-1 compounds, i.e., it is the one most strongly hydrophilic. The hydrophilia is not achieved, as in the compound referred to as iohexol, by introduction of an additional hydroxyalkyl function (which reduces the iodine content and increases viscosity and osmolality), but is the surprising result of a new steric arrangement of substituents on the iodized aromatic compounds.
Hydrophilia is considered an important requirement for reducing the non-osmolality-related side effects that are observed with intravenous injection (Dawson, P.; Clau~, W.:
Contrast Media in Practice, Springer Verlag Berlin Heidelberg 1993, pages 11-12). In particular, nausea and vomiting, as well as allergy-like reaction up to major anaphylactic shock, are part of this. Other test results which show especially good general compatibility are obtained in biochemical, biological and toxicological (Tab. 2) studies.
Tab.2: Studies of lethal doses after intravenous injection in rats (90-110 g), Concentration of the contrast medium solutions corresponding to 300 mg of iodine/ml, Injection rate of 2 ml/min, Dose corresponding to g of iodine/kg of body weight;
Indication of the number of animals that have died/total number of animals CA 0221~38~ 1997-09-1 Test Dose 1: Dose 2: Dose 3: All Substance 12 g of 15 g of 18 g ofDosages I/kg I/kg I/kg (%) Example 1 0/4 2/4 2/4 33 Iopamidol 2/4 1/4 4/4 58 Iopromide 1/4 3/4 4/4 67 Iomeprol 2/3 3/3 3/3 89 Studies of organ toxicity reveal better compatibility of the compounds according to the invention, as is of increasing importance in computer tomography. Elimination is carried out especially fast and completely. Finally, the compounds according to the invention exhibit high stability under different storage conditions. As a result, excellent purity is also ensured under operational conditions and at the time of use.
The invention therefore relates to the new compounds characterized in the claims.
Computer tomography with high-speed devices is an imaging diagnostic process which generates extraordinarily detailed and exact data very quickly. With high patent capacity per unit of time, it is an economical process despite expensive technology.
The contrast media according to the invention contribute significantly to improving the process by allowing operations that are largely undisturbed by side effects despite fast injection and high dosage levels. At the same time, the CA 022l~38~ l997-09-l~
properties of the contrast media also contribute to the gentle treatment of often very seriously ill patients.
The invention therefore also relates to the use of the compounds characterized in the claims for the production of tools for diagnosis by computer tomography.
The compounds are very well suited for urography because of the good renal elimination of the compounds according to the invention in combination with good compatibility even in seriously ill patients.
Beeause of their good compatibility, the eompounds aeeording to the invention are also suitable for angiography, myelography, and interventional radiology. The invention therefore also relates to the use of the eompounds eharaeterized in the elaims for the produetion of tools for urography, for angiography, for myelography, and for interventional radiology.
For purposes of use, the contrast medium substance is dissolved at different concentrations in sterile, pyrogen-free water. The concentrations correspond to about 20 mg to 1 g of contrast medium substancetml, corresponding to about 10 to 500 mg of iodine/ml. Concentrations corresponding to 100-400 mg of iodine/ml are preferred for especially advantageous parenteral applications. Physiologically compatible buffers such as sodium carbonate, tris(tris-hydroxymethylaminomethane)/HCl, bicarbonate, phosphate, citrate, etc. can be added in the usual way to the contrast medium solutions. The buffer concentration can be 1-100 mmol/liter. The buffer is preferably adjusted to approximately physiologic pH levels of between 5 and 8. Complexing agents, such as EDTA, DTPA and/or their salts with physiologically compatible ions such as sodium, potassium, magnesium, calcium, lysine, etc. can also be added to the contrast medium solutions, as well as pharmacologically active substances (vasodilators, anticoagulants, etc.), which improve compatibility or alter the pharmacokinetics in a desired way.
Another use of the contrast media in question can be oral intake for visualization of the gastrointestinal tract. For this purpose, the contrast medium can be offered as powder for the production of a solution before use or as a concentrate or as finished solution. In any case, the contrast medium can contain physiologically compatible buffers, stabilizers, substances for matching the osmolality, pharmacologically effective substances, preservatives, flavoring substances and/or swelling substances.
In general, the tools according to the invention are dosed in amounts of 2 to 1500, preferably 20 to 1000 ml/study.
The decanting of the contrast medium solutions is done in glass tanks or inert plastic containers in volumes of a few milliliters per unit up to about 1 liter, as are usual for x-ray investigations. The solutions can either be sterilized by filtration and decanted in sterile containers under sterile conditions and sealed in a sterile way, or the solutions can be heat-sterilized in the containers.
The dosage per patient is also a few milliliters to at most about 1 liter, and the contrast medium dose corresponds to about 1-150 g of iodine per patient, preferably 20-100 g of iodine.
CA 022l~38~ l997-09-l~
The invention therefore also relates to the pharmaceutical agents characterized in the claims.
The invention also relates to a process for the production of compounds of general formula I, characterized in that a compound of general formula II
O~Z
X~~\J~N~NH ~ ~~X3 (Il), in which X1, XZ and X3 stand for hydroxy protective groups and Z
stands for a reactive acid or ester radical, is reacted in a polar solvent or a solvent mixture, containing at least one polar solvent, at a temperature of 0~C to 120~C, optionally in the presence of an auxiliary base with diethanolamine or N-methylamino-propanediol and then the hydroxy protective groups are cleaved off in a known way.
As reactive acid or ester radical Z, especially halogen atoms, such as chlorine, bromine or iodine atoms, are considered.
The process can also be performed, however, if Z stands for the azide radical, the alkoxycarbonyloxy radical or the radical of a reactive ester group (e.g., an alkyl-0, aryl-O or N-C-CH2 radical). Preferred radicals Z are halogen atoms, especially preferred is the chlorine atom.
CA 0221~38~ 1997-09-1 As hydroxy protective groups, those groups are considered that are suitable, as is generally known, for intermediate hydroxy group protection, i.e., that can be easily introduced and later with reformation of the finally desired free hydroxy group, also easily cleaved off again. Preferred is protection by esterification, e.g., by introduction of the benzoyl, alkanoyl or acyl radical, especially of the acetyl or the acetoxyacetyl radical. The vicinal hydroxy groups can also be protected jointly by introduction of the cyclic sulfite ester or of the carbonic acid ester. Suitable protective groups are also ether groups, such as, e.g., benzyl, di- and tripehnylmethylether groups, as well as acetal and ketal groups withj e.g., acetaldehyde or acetone.
The compounds of general formula II with the mentioned amines is performed in slightly polar to polar solvents optionally in the presence of auxiliary bases. If Z stands for a halogen atom, the reaction is always performed in the presence of an auxiliary base. As auxiliary bases, there are tertiary amines, e.g., trialkylamines or pyridine, or inorganic bases, such as alkali or alkaline-earth hydroxides, carbonates or hydrogen carbonates, e.g., sodium hydroxide, sodium bicarbonate, potassium carbonate, sodium carbonate, calcium hydroxide or magnesium hydroxide. Sodium carbonate, potassium carbonate, triethylamine and tributylamine are preferably used. The auxiliary base, which bonds to the hydrogen halide that has developed in the reaction, is selected in such a way that the salt of the auxiliary base precipitates as crystals as CA 0221~38~ 1997-09-1 quantitatively as possible in the correspondingly selected solvent and can be separated by simple filtration. The temperature in the reaction can be between 0~C and 120~C, preferably between 30~C and 90~C. Preferred solvents are acetone, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, dimethylacetamide and dimethylformamide and their mixtures as well as their mixtures with water.
The cleavage of the hydroxy protective groups is carried out according to methods that are familiar to one skilled in the art.
They can be carried out with the working-up and isolation of the reaction products without isolating the intermediate product.
They can also be performed, however, in a separate reaction stage. Acyl protective groups can be cleaved, for example, by alkaline and acetal, ketal or ether protective groups by acid hydrolysis. The alkaline or acid hydrolysis, especially the alkaline hydrolysis, is preferably performed in water. Alkali hydroxides, preferably sodium hydroxide, are used as base.
The inorganic and/or organic salts, which develop in the course of the reaction, are separated by treating reaction solutions with ion exchangers or adsorbents (e.g.: Diaion or Amberlite XAD-2 or -4), and the salt-free products are further purified by crystallization from organic solvents, especially ethanol.
The compounds of general formula II are produced starting from the compounds 5-amino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxy-propyl)-monoamide or 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxy-propyl)-monoamide described in EP 308364 in CA 0221~38~ 1997-09-1 the way known to one skilled in the art (e.g.: Methoden der organischen Chemie [Methods of Organic Chemistry] (Houben-Weyl), Vol. E5, Carbonsauren und Carbonsaure Derivate [Carboxylic Acids and Carboxylic Acid Derivatives], Thieme Verlag, Stuttgart, New York, 1985).
For the production of especially preferred compounds with Z
meaning a chlorine atom, the reaction is performed, for example, in nonpolar to polar, preferably moderately polar, aprotic solvents with organic and/or inorganic acid halides, preferably acid chlorides. The reaction is performed at temperatures of between 0~C and 120~C, preferably at 50~ to 90~C. The reaction can be carried out in the presence or absence of basic catalysts such as pyridine or 4-dimethylaminopyridine.
The reaction preferably is performed in the presence of a basic catalyst in a slightly polar aprotic solvent, from which the acid chloride of general formula I precipitates as crystals and can be isolated easily and with good yield and purity.
Preferred solvents are ethyl acetate, isopropyl acetate, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, dimethylacetamide and dimethylformamide.
If 5-amino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxy-propyl)-monoamide is used as starting material, it can be reacted either first with acetoxyacetyl chloride and then with, e.g., the inorganic acid halide thionyl chloride to the intermediate 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxyacetoxypropyl)-amide-chloride or first with thionyl chloride and then with acetoxyacetyl chloride to the intermediate CA 022l~38~ l997-09-l~
5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-t2-oxo-1,3,2-dioxathiolan-4-ylmethyl)-amide-chloride.
The following examples are to explain the object of the invention, without intending that it be limited to these examples.
CA 0221~38~ 1997-09-1 ~xample 1: 5-Hydroxyacetylamino-2,4,6-triiodoisophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl~]-diamide ~.1. Production of acid chlorides 1.1.1. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride 200 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxy-propyl)-monoamide is suspended in 200 ml of dioxane, 114.4 g of acetoxyacetyl chloride is added, and the suspension is heated to 90~C. A solution develops. After about 2 hours, the TLC in, e.g., methylene chloride/methanol 10:3 shows that the amino group of the starting compound is quantitatively acylated.
49.84 g of thionyl chloride is added and stirred for another 2 hours at 90~C. The TLC in the above system then shows the quantitative reaction to acid chloride. The reaction solution is reduced by distillation in a vacuum to about one third of its volume, 350 ml of ethyl acetate is added, and it is stirred for 2 hours at room temperature. Ample crystallizate develops. The latter is filtered off, washed with ethyl acetate and dried in a vacuum at 50~C. The yield is 212 g = 91% of theory.
1.1.2. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride 71.6 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxy-propyl)-monoamide is suspended in 71.6 ml of ethyl CA 0221~38~ 1997-09-1 acetate, 34.71 g of acetoxyacetyl chloride is added, and the suspension is stirred for 4 hours at an internal temperature of about 82~C. Then, 23.8 g of thionyl chloride is added, and it is stirred for another 5 hours at about 85~C internal temperature.
The suspension is then diluted with 200 ml of ethyl acetate, cooled to room temperature, the crystallizate is filtered off, washed with ethyl acetate and dried in a vacuum at 50~C. Yield 75.5 g = 90.5% of theory.
1.1.3. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride 71.6 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxypropyl)-monoamide is suspended in 71.6 ml of ethyl acetate, 34.71 g of acetoxyacetyl chloride and 0.54 g of 4-dimethylaminopyridine (DMAP) is added, and the suspension is stirred for 2 hours at an internal temperature of about 82~C.
Then, 23.8 g of thionyl chloride is added, and it is stirred for another 5 hours at about 85~C internal temperature. The suspension is then diluted with 200 ml of ethyl acetate, cooled to room temperature, the crystallizate is filtered off, washed with ethyl acetate and dried in a vacuum at 50~C. Yield 71.8 g = 86~ of theory.
1.1.4. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride 71.6 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxy-propyl)-monoamide is suspended in 71.6 ml of diethylene CA 022l~38~ l997-09-l~
glycol dimethyl ether, 27.31 g of acetoxyacetyl chloride is added, and the suspension is stirred for 8 hours at an internal temperature of about 95~C. A solution develops. Then, 29.74 g of thionyl chloride is added, and it is stirred for another 2.5 hours at an internal temperature of about 83~C. The solution is then diluted with 200 ml of ethyl acetate, cooled to room temperature, the crystallizate is filtered off, washed with ethyl acetate and dried in a vacuum at 50~C. Yield 67.2 g = 80.5% of theory.
1.1.5. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono- -(2,3-diacetoxypropyl)-amide-chloride 357 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxypropyl)-monoamide is refluxed in 1.6 l of dichloroethane with 178 ml of thionyl chloride for 1.5 hours. A solution develops from the suspension. The latter is cooled to room temperature and absorptively precipitated with saturated sodium bicarbonate solution until the aqueous phase reacts in a weakly alkaline manner. The phases are separated, the organic phase is concentrated by evaporation to oil, the oil is dissolved in of ethyl acetate, mixed with 204 g of acetoxyacetyl chloride and refluxed for about 8 hours. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride increasingly precipitates as crystals from the solution. It is cooled to room temperature, suctioned off, washed with ethyl acetate and dried in a vacuum at 50~C. The yield is 308 g =
72.3% of theory.
CA 0221~38~ 1997-09-1 1.1.6. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-(2-oxo-1,3,2-dioxathiolan-4-ylmethyl)-monoamide-chloride 119.08 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxy-propyl)-monoamide is suspended in 1070 ml of ethyl acetate, 85.44 g of thionyl chloride is added, and the suspension is heated to boiling. After about 20 minutes, a clear solution develops. 90 g of acetoxyacetyl chloride is added to this solution in the course of about 10 minutes and further stirred at boiling temperature. After about 4 hours, the product crystallizes out from the boiling reaction solution. After about 8 hours, the reaction is completed. It is cooled to room temperature, the crystallizate is filtered off, washed with ethyl acetate and dried at 50~C in a vacuum. Yield 97.86 g = 67.24% of theory.
1.1.7. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-(2-oxo-1,3,2-dioxathiolan-4-ylmethyl)-monoamide-chloride 63.1 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxypropyl)-monoamide is suspended in 120 ml of ethyl acetate, 12.5 g of thionyl chloride is gradually added at about 5-10~C and stirred for 3 hours at room temperature. The suspension is then heated to boiling, 41 g of acetoxyacetyl chloride is added in drops in the course of one hour, 0.6 g of 4-dimethylaminopyridine is added and refluxed for 3 hours. The suspension changes into a solution. After the end of this time, 23.8 g of thionyl chloride is added in drops to this solution in the course of 30 minutes and then refluxed for 2 hours. In this CA 0221~38~ 1997-09-1 time, the product increasingly precipitates as crystallizate from the solution. 200 ml of ethyl acetate is added, refluxed for another 30 minutes, then cooled to room temperature, the crystallizate is suctioned off, washed with ethyl acetate and dried for 24 hours at 50~C in a vacuum. Yield: 58.5 g = 73 . 5%
of theory.
1.1.8. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxyacetoxypropyl)-amide-chloride 63.1 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxypropyl)-monoamide is suspended in 100 ml of ethyl acetate, 60.4 g of acetoxyacetyl chloride and 1 g of 4-dimethylaminopyridine are added, and the suspension is refluxed.
The suspension gradually changes into a solution. After about 4 hours, the acylation is complete. 14. 7 ml of thionyl chloride is added and refluxed for another 5 hours. The product begins to precipitate as crystals. To increase the crystallizate, another 200 ml of ethyl acetate is added, cooled to room temperature and stirred for 2 more hours. The crystallizate is suctioned off, washed with ethyl acetate and dried at 50~C in a vacuum.
Yield: 64.8 g = 68.2~ of theory CA 0221~38~ 1997-09-1 1.2. Production of 5-hydroxyacetylamino-2,4,6-triiodoisophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide 1.2.1. 500 g of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride (Example 1.1.1) is suspended in 1300 ml of acetone, 69.2 g of N-methylaminopropanediol and 188.55 g of Na2C03 x 10 H20 are added, and the suspension is refluxed for 1 hour. The inorganic salts are filtered off, and the filtrate is mixed at 50~C in the course of about 1 hour with a total of 100 ml of 50% by weight of sodium hydroxide solution. The solution is then brought to pH 7 with 27 ml of 11.5N hydrochloric acid, desalinated on ion exchangers, the aqueous eluate is concentrated by evaporation in a vacuum to an oil, and the latter crystallizes from 2 l of ethanol in boiling heat.
Yield: 295.6 g = 63.5% of theory 1.2.2. 90 g of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride (Example 1.1.2) was dissolved in 260 ml of dioxane, 47.3 g of Na2C03 x 10 H20 and 13.86 g of N-methylaminopropanediol were added and stirred for 3 hours at room temperature. The inorganic salts were suctioned off, the filtrate was concentrated by evaporation in a vacuum to an oil, this oil was dissolved in 200 ml of water and mixed at 40~C gradually with 35 ml of 50% by weight of sodium hydroxide solution. The aqueous solution was then brought to pH
CA 0221~38~ 1997-09-1 7 with about 6 ml of 11.5N hydrochloric acid, desalinated on ion exchangers, the aqueous eluate was concentrated by evaporation in a vacuum to an oil, and the latter was crystallized from 350 ml of ethanol in boiling heat. Yield: 58.1 g = 68% of theory 1.2.3. 100 g of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-(2-oxo-1,3,2-dioxathiolan-4-ylmethyl)-monoamide-chloride (Example 1.1.7) is suspended in 500 ml of acetone, 39.5 g of soda decahydrate and 14.5 g of methylaminopropanediol are added and refluxed for 1 hour. It is then cooled to room temperature, the inorganic salts are filtered off, the filtrate is largely concentrated by evaporation under reduced pressure, and the residue is dissolved in 300 ml of water. At 40~C, the aqueous solution is gradually mixed with about 20 ml of 50% by weight of NaOH and in this case the pH is held between 10 and 12. The basic solution is then desalinated on a cation exchanger and an anion exchanger, the aqueous eluate is concentrated by evaporation to an oil, and the latter is crystallized from about 300 ml of ethanol. Yield: 61.5 g = 63% of theory Example 2: 5-Hydroxyacetylamino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxypropyl)-[N-bis(2-hydroxyethyl)]-diamide 2.1. 100 g of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-(2-oxo-1,3,2-dioxathiolan-4-ylmethyl)-monoamide-chloride (Example 1.1.7) is suspended in 500 ml of acetone, 39.5 g of soda decahydrate and 14.5 g of diethanolamine are added and refluxed CA 0221~38~ 1997-09-1 for 1 hour. It is then cooled to room temperature, the inorganic salts are filtered off, the filtrate is largely concentrated by evaporation under reduced pressure, and the residue is dissolved in 300 ml of water. At 40~C, the aqueous solution is gradually mixed with about 20 ml of 50% by weight of NaOH and in this case, the pH is held between 10 and 12. The basic solution is then desalinated on a cation exchanger and an anion exchanger, the aqueous eluate is concentrated by evaporation to an oil, and the latter is crystallized from about 300 ml of ethanol. Yield:
68.6 g = 70.3% of theory 2.2. 95 g of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxyacetoxypropyl)-amide-chloride (Example 1.1.8) is suspended in 500 ml of acetone, 31.5 g of soda decahydrate and 11.6 g of diethanolamine are added and refluxed for 1 hour. It is then cooled to room temperature, the inorganic salts are filtered off, the filtrate is largely concentrated by evaporation under reduced pressure, and the residue is dissolved in 300 ml of water. At 40~C, the aqueous solution is gradually mixed with about 16 ml of 50% by weight of NaOH, and in this case, the pH is held between 10 and 12. The basic solution is then desalinated on a cation exchanger and an anion exchanger, the aqueous eluate is concentrated by evaporation to an oil, and the latter is crystallized from about 300 ml of ethanol. Yield:
51 g = 65.7% of theory.
CA 0221~38~ 1997-09-1 Example 3: Solution for injection for computer tomography 683.7 g of the anhydrous and pyrogen-free substance according to Example 1 is added to 500 ml of pyrogen-free water containing 10 mmol of tris(tris-hydroxymethylaminomethane) and 100 mg of Na2Ca EDTA, dissolved in heat, cooled, adjusted to pH
6.8 with lN HCl and filled with pyrogen-free water to 1000 ml.
The solution is bottled in portions of 200 ml in glass flasks holding 250 ml, which are tightly sealed with rubber stoppers, flanged and heat-sterilized for 20 minutes at 121~C.
Example 4: Use in computer tomography The product according to Example 3 is intravenously injected in patients at a dose of 2 ml/kg at an injection rate of 4 ml/sec. 25 seconds after the beginning of the injection, the area of the liver is scanned from cranial to caudal with a layer thickness of 0.5 cm and a table feed rate of 0.7 cm/sec for a period of 30 seconds in the case of respiratory arrest with a spiral CT. A visualization of the abdomen in the area of the liver develops in 30 layers, in which areas well supplied with blood show a high radiation absorption. In this way, certain diseases of the liver can be revealed significantly better than without contrast media.
Example 5: Use in computer tomography 30 ml of the product according to Example 3 is diluted with 970 ml of drinking water. The solution is drunk slowly within 1 hour before a study of the abdomen with the aid of computer tomography. Stomach and intestines can be better defined by the contrast medium in computer tomography.
X-Ray Contrast Media for Computer Tomography and Urography The invention relates to the object characterized in the claims, i.e., new iodine-containing x-ray contrast media, their production and uses. The new compounds solve important problems in contrast-enhanced computer tomography. Further, they are very well suited for urography.
Contrast media are indispensable for medical diagnostic radiology. Many radiological studies cannot yield useful information without contrast media. Urography, visualization of the blood vessels and cardiac ventricles, the subarachnoid spaces, the lymph tracts, and the gastrointestinal tract, and numerous pathological processes in computer tomography can be mentioned.
The first intravascularly injectable, relatively universally usable iodized x-ray contrast media were produced more than 50 years ago. These products, originally salts of mono-iodized organic acids, have since been improved in many ways as regards their effectiveness and compatibility. The best contrast media now available carry 3 or 6 iodine atoms per molecule instead of originally a single iodine atom; they are no longer salts, but rather neutral, sugar-like substances, and the osmolality of their solutions is, in the most advantageous case, no longer tenfold or more higher than that of blood; rather, it is blood-isotonic despite extremely high concentrations.
CA 0221~38~ 1997-09-1~
The compatibility of the new contrast media seemed at first to fulfill all wishes simultaneously. Thus, the same products were used for very different applications, such as intravenous injection, arteriography, venography, cardiography, myelography, the visualization of the gastrointestinal tract, and many other body cavities. Only the contrast medium concentration in the solution and the injected or infused volumes were adapted to the special test. A well-known product was dubbed Omnipaque(R) to reflect this concept, i.e., it was supposed to be suitable for all indications.
In contrast, especially in the last 10 years, there has been further development of individual contrast medium-enhanced x-ray methods, with increasingly more specific requirements imposed on the contrast media used in each case. Vasography is performed not only for diagnostic purposes, but at the same time is being used more and more often as a less-invasive means of access to therapeutic interventions for pathological changes in the body that are otherwise only surgically accessible. For example, as part of angiographic tests with visualization of the blood vessels by catheters through which the contrast media are injected, simultaneously and with the same catheters, stenoses of the coronary arteries can be dissolved, and blood vessels supplying tumors can be enlarged without the chest having to be opened up surgically. Clots can be dissolved by specific selective infusion of thrombolytic agents into the affected blood vessels, blood vessels supplying tumors can be sealed by selective injection of microparticles or certain embolisates that CA 0221~38~ 1997-09-1~
consolidate in the blood, or internal bleeding can be controlled with the last-mentioned process or vascular anomalies in the brain can be treated. In this connection, contrast media are injected first for diagnostic purposes and then very often repeated to monitor the treatment process in certain vascular regions (interventional radiology). Since these procedures are performed in most cases in older, seriously ill patients, extreme requirements with respect to vascular compatibility and --because of the total dose being cumulative -- also with respect to general compatibility are to be imposed on the contrast media.
However, other requirements are less critical: the modern image-processing techniques make it possible, in most cases, to operate with lower contrast medium concentrations, so that the desired low viscosity of the solutions is now easier to achieve.
Further, it is known that nausea and vomiting, as well as allergy-like reactions occur more rarely after arterial administration of contrast media by catheter than after intravenous injection by needle. In this regard as well, the contrast media for vascular diagnosis with the aid of a catheter are therefore not to be judged as critically as intravenously injectable products.
At this time, certainly, the so-called nonionic dimeric (hexaiodized) contrast media, which are distinguished particularly by excellent vascular compatibility, are to be evaluated as optimum for most arterial and direct venous vasographies.
CA 0221~38~ 1997-09-1~
There are similar special requirements, for example, on contrast media for the visualization of other body regions. Very good neural compatibility is indispensable for the visualization of the vertebral canal (myelography). The contrast medium should also exhibit high enough viscosity that dilution by bodily fluids is carried out as slowly as possible. The same requirement for slow dilution is imposed in the visualization of joint cavities.
In diagnostic radiology of the gastrointestinal tract, it is a requirement that the contrast medium exhibit an acceptable taste, be diluted slightly by osmosis, and not trigger any diarrhea. In past years, however, the above-mentioned processes have become less important since there are now other diagnostic methods with which satisfactory results are achieved in many cases.
Computer tomography is of extraordinary importance that is even increasing even more due to recent technical developments.
Unlike in other x-ray techniques, it is not an area (for example, the chest) that is irradiated, but only a disk a few millimeters thick, for example, through the skull or body, and this disk is calculated and presented as a sectional image. While computer tomography originally required about 20 seconds to obtain the data for such a disk, this process is completed in 1 second or 50 milliseconds in modern devices. At the same time, the patient can be moved through the measuring device, so that, for example, in 30 seconds, 30 layers in 5 mm layer thickness are covered and thus a body section that is 15 cm in length.
After intravenous injection, the usual contrast media can reveal the blood vessels and show the perfusion of vessels, CA 0221~38~ 1997-09-1~
organs and tissues, as well as the permeability of capillaries by overflow from the blood space into the considerably larger intercellular space of the tissue.
Many pathological changes can be detected especially well during the first passage of the contrast medium after quick intravenous injection since the distribution differences in the healthy tissue are the most pronounced at that point. It is clear that quick computer tomographs, which cover entire body sections within a few seconds or display the timing of the contrast medium's passage through a certain region by fast repeated images, can reveal these contrast medium distribution differences best of all. Quick computer tomography has therefore become an increasingly more important and increasingly more widely used tool of medical diagnosis. Approximately half the amounts of x-ray contrast media now used are employed in computer tomography.
The method of application and the requirements imposed on contrast media in computer tomography differ significantly from those for catheter arteriography and venography. To achieve sufficient contrast, large amounts of contrast media must be quickly injected intravenously through comparatively narrow cannulae. Amounts of contrast media corresponding to 15-45 g of iodine per single injection are necessary. It may be necessary -- or it is even usual - to repeat the individual injections at intervals of a few minutes. In the case of efficient quick computer tomographs, the injection rate is generally 1-5 ml/sec or more (Small, W. C.; Nelson, R. C.; Bernadino, M. E.; Brummer, L. T.: Contrast-Enhanced Spiral CT of the Liver: Effects of Different Amounts and Injection Rates of Contrast Material on Early Contrast Enhancement. AJR 163, 87-92, 1994).
To be able to inject these amounts quickly, the contrast medium solutions must be sufficiently thin at high iodine concentration. The contrast medium side effects that are most common and most disruptive after intravenous administration (Dawson, P.; Clau~, W., Edts: Contrast Media in Practice, Springer Verlag Berlin Heidelberg 1993, pp. 107-109), such as nausea, vomiting and allergy-like reactions, should occur as seldom as possible. Extremely high dosages must be tolerated by all organs despite corresponding previous injury in many patients.
It should be possible to produce the contrast media at reasonable cost so as to not unnecessarily restrict the availability of the relatively economical computer tomographic examination methods per se. Since intravenous injection only rarely results in irritation of the local veins or after dilution in the heart, or even irritation of the arteries, no extreme requirements are imposed on the local vascular compatibility of the contrast media for computer tomography. Contact with the central nervous system is possible only after at least 10-fold dilution by the general blood circulation, so that neural compatibility should be completely satisfactory for almost all intravascular contrast media.
Requirements similar to those of computer tomography are also to be imposed on contrast media for elimination urography.
CA 0221~38~ 1997-09-1~
Also, these contrast media are quickly administered intravenously. The specific diseases of the patients for whom urography is to be performed, as well as the need for high-contrast and complete radiological visualization of the urinary passages, impose additional requirements on compatibility, elimination, and diuretic effects.
Many of the now available water-soluble x-ray contrast media and the new developments in recent years attempt to meet the requirements of widely varying classes of applications simultaneously, while others are specially tailored to the angiographic application. Some exhibit widely varied deficiencies and are optimally suitable for none of the above-mentioned applications. The substances (iopentol, iohexol, ioversol) contain, for example, a relatively small iodine content, which results in elevated viscosity of their solutions.
Simultaneously, osmolality rises to an undesirable extent.
Nonionic dimeric contrast media (iotrolan, iodixanol) are desirably blood-isotonic, but simultaneously also viscous. New contrast media with very high iodine content (for example, the compounds mentioned in Patent Specifications US 5047228 and US
5019371) seem to combine low osmolality and viscosity in an ideal way. Inadequate water-solubility and problems of compatibility, however, have thus far prevented successful development.
The group of contrast media thus far best suited to the requirements of computer tomography consists of chemically very closely related compounds: iopromide, iopamidol, and iomeprol.
They are distinguished by low viscosity (for fast injection) with CA 0221~38~ 1997-09-1~
low osmolality (for low cardiovascular system stress) and acceptable general and organ compatibility. Thus, they come closest to meeting the requirements of contrast media that can be injected intravenously quickly and in high doses.
The steady development of computer tomography and the repeated study of very seriously ill patients require, however, further improvement, especially of the compatibility of the x-ray contrast media provided for this application, without the iodine content being reduced as in the other mentioned substances and thus viscosity being increased and injectability deteriorating.
The object of the invention is thus to make available such compounds and tools, as well as to provide a process for their production. The achievement of this object is done by the objects characterized in the claims.
It has been found that two new compounds show surprisingly advantageous properties, especially when used in computer tomography. In this case, these are compounds of general formula I
IR' O~N'R2 ~ ~ NH ~ OH
(I) in which either CA 0221~38~ 1997-09-1~
-R1 stands for the methyl radical and R2 stands for the 2,3-dihydroxypropyl radical or -R1 and R2 in each case stand for the 2-hydroxyethyl radical.
While the osmolality, viscosity, and iodine content are very similar to those of the structural isomeric compounds iopamidol and iomeprol, a surprisingly high hydrophilia of the compounds according to the invention can be seen (Tab. 1).
Tab. 1: Butanol/water (buffer pH 7) -- distribution coefficient of different contrast media, n = 4, average value + standard deviation and iodine content of the molecule Distribution Iodine Content (%) Coefficient Example 1 0.069 + 0.011 49 Iopromide - 0.149 + 0.011 4%
Iopamidol 0.089 + 0.014 49 Iomeprol 0.105 + 0.006 49 Iohexol 0.082 + 0.005 46 The substance according to Example 1 exhibits the smallest distribution coefficient of the structurally comparable CA 0221~38~ 1997-09-1 compounds, i.e., it is the one most strongly hydrophilic. The hydrophilia is not achieved, as in the compound referred to as iohexol, by introduction of an additional hydroxyalkyl function (which reduces the iodine content and increases viscosity and osmolality), but is the surprising result of a new steric arrangement of substituents on the iodized aromatic compounds.
Hydrophilia is considered an important requirement for reducing the non-osmolality-related side effects that are observed with intravenous injection (Dawson, P.; Clau~, W.:
Contrast Media in Practice, Springer Verlag Berlin Heidelberg 1993, pages 11-12). In particular, nausea and vomiting, as well as allergy-like reaction up to major anaphylactic shock, are part of this. Other test results which show especially good general compatibility are obtained in biochemical, biological and toxicological (Tab. 2) studies.
Tab.2: Studies of lethal doses after intravenous injection in rats (90-110 g), Concentration of the contrast medium solutions corresponding to 300 mg of iodine/ml, Injection rate of 2 ml/min, Dose corresponding to g of iodine/kg of body weight;
Indication of the number of animals that have died/total number of animals CA 0221~38~ 1997-09-1 Test Dose 1: Dose 2: Dose 3: All Substance 12 g of 15 g of 18 g ofDosages I/kg I/kg I/kg (%) Example 1 0/4 2/4 2/4 33 Iopamidol 2/4 1/4 4/4 58 Iopromide 1/4 3/4 4/4 67 Iomeprol 2/3 3/3 3/3 89 Studies of organ toxicity reveal better compatibility of the compounds according to the invention, as is of increasing importance in computer tomography. Elimination is carried out especially fast and completely. Finally, the compounds according to the invention exhibit high stability under different storage conditions. As a result, excellent purity is also ensured under operational conditions and at the time of use.
The invention therefore relates to the new compounds characterized in the claims.
Computer tomography with high-speed devices is an imaging diagnostic process which generates extraordinarily detailed and exact data very quickly. With high patent capacity per unit of time, it is an economical process despite expensive technology.
The contrast media according to the invention contribute significantly to improving the process by allowing operations that are largely undisturbed by side effects despite fast injection and high dosage levels. At the same time, the CA 022l~38~ l997-09-l~
properties of the contrast media also contribute to the gentle treatment of often very seriously ill patients.
The invention therefore also relates to the use of the compounds characterized in the claims for the production of tools for diagnosis by computer tomography.
The compounds are very well suited for urography because of the good renal elimination of the compounds according to the invention in combination with good compatibility even in seriously ill patients.
Beeause of their good compatibility, the eompounds aeeording to the invention are also suitable for angiography, myelography, and interventional radiology. The invention therefore also relates to the use of the eompounds eharaeterized in the elaims for the produetion of tools for urography, for angiography, for myelography, and for interventional radiology.
For purposes of use, the contrast medium substance is dissolved at different concentrations in sterile, pyrogen-free water. The concentrations correspond to about 20 mg to 1 g of contrast medium substancetml, corresponding to about 10 to 500 mg of iodine/ml. Concentrations corresponding to 100-400 mg of iodine/ml are preferred for especially advantageous parenteral applications. Physiologically compatible buffers such as sodium carbonate, tris(tris-hydroxymethylaminomethane)/HCl, bicarbonate, phosphate, citrate, etc. can be added in the usual way to the contrast medium solutions. The buffer concentration can be 1-100 mmol/liter. The buffer is preferably adjusted to approximately physiologic pH levels of between 5 and 8. Complexing agents, such as EDTA, DTPA and/or their salts with physiologically compatible ions such as sodium, potassium, magnesium, calcium, lysine, etc. can also be added to the contrast medium solutions, as well as pharmacologically active substances (vasodilators, anticoagulants, etc.), which improve compatibility or alter the pharmacokinetics in a desired way.
Another use of the contrast media in question can be oral intake for visualization of the gastrointestinal tract. For this purpose, the contrast medium can be offered as powder for the production of a solution before use or as a concentrate or as finished solution. In any case, the contrast medium can contain physiologically compatible buffers, stabilizers, substances for matching the osmolality, pharmacologically effective substances, preservatives, flavoring substances and/or swelling substances.
In general, the tools according to the invention are dosed in amounts of 2 to 1500, preferably 20 to 1000 ml/study.
The decanting of the contrast medium solutions is done in glass tanks or inert plastic containers in volumes of a few milliliters per unit up to about 1 liter, as are usual for x-ray investigations. The solutions can either be sterilized by filtration and decanted in sterile containers under sterile conditions and sealed in a sterile way, or the solutions can be heat-sterilized in the containers.
The dosage per patient is also a few milliliters to at most about 1 liter, and the contrast medium dose corresponds to about 1-150 g of iodine per patient, preferably 20-100 g of iodine.
CA 022l~38~ l997-09-l~
The invention therefore also relates to the pharmaceutical agents characterized in the claims.
The invention also relates to a process for the production of compounds of general formula I, characterized in that a compound of general formula II
O~Z
X~~\J~N~NH ~ ~~X3 (Il), in which X1, XZ and X3 stand for hydroxy protective groups and Z
stands for a reactive acid or ester radical, is reacted in a polar solvent or a solvent mixture, containing at least one polar solvent, at a temperature of 0~C to 120~C, optionally in the presence of an auxiliary base with diethanolamine or N-methylamino-propanediol and then the hydroxy protective groups are cleaved off in a known way.
As reactive acid or ester radical Z, especially halogen atoms, such as chlorine, bromine or iodine atoms, are considered.
The process can also be performed, however, if Z stands for the azide radical, the alkoxycarbonyloxy radical or the radical of a reactive ester group (e.g., an alkyl-0, aryl-O or N-C-CH2 radical). Preferred radicals Z are halogen atoms, especially preferred is the chlorine atom.
CA 0221~38~ 1997-09-1 As hydroxy protective groups, those groups are considered that are suitable, as is generally known, for intermediate hydroxy group protection, i.e., that can be easily introduced and later with reformation of the finally desired free hydroxy group, also easily cleaved off again. Preferred is protection by esterification, e.g., by introduction of the benzoyl, alkanoyl or acyl radical, especially of the acetyl or the acetoxyacetyl radical. The vicinal hydroxy groups can also be protected jointly by introduction of the cyclic sulfite ester or of the carbonic acid ester. Suitable protective groups are also ether groups, such as, e.g., benzyl, di- and tripehnylmethylether groups, as well as acetal and ketal groups withj e.g., acetaldehyde or acetone.
The compounds of general formula II with the mentioned amines is performed in slightly polar to polar solvents optionally in the presence of auxiliary bases. If Z stands for a halogen atom, the reaction is always performed in the presence of an auxiliary base. As auxiliary bases, there are tertiary amines, e.g., trialkylamines or pyridine, or inorganic bases, such as alkali or alkaline-earth hydroxides, carbonates or hydrogen carbonates, e.g., sodium hydroxide, sodium bicarbonate, potassium carbonate, sodium carbonate, calcium hydroxide or magnesium hydroxide. Sodium carbonate, potassium carbonate, triethylamine and tributylamine are preferably used. The auxiliary base, which bonds to the hydrogen halide that has developed in the reaction, is selected in such a way that the salt of the auxiliary base precipitates as crystals as CA 0221~38~ 1997-09-1 quantitatively as possible in the correspondingly selected solvent and can be separated by simple filtration. The temperature in the reaction can be between 0~C and 120~C, preferably between 30~C and 90~C. Preferred solvents are acetone, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, dimethylacetamide and dimethylformamide and their mixtures as well as their mixtures with water.
The cleavage of the hydroxy protective groups is carried out according to methods that are familiar to one skilled in the art.
They can be carried out with the working-up and isolation of the reaction products without isolating the intermediate product.
They can also be performed, however, in a separate reaction stage. Acyl protective groups can be cleaved, for example, by alkaline and acetal, ketal or ether protective groups by acid hydrolysis. The alkaline or acid hydrolysis, especially the alkaline hydrolysis, is preferably performed in water. Alkali hydroxides, preferably sodium hydroxide, are used as base.
The inorganic and/or organic salts, which develop in the course of the reaction, are separated by treating reaction solutions with ion exchangers or adsorbents (e.g.: Diaion or Amberlite XAD-2 or -4), and the salt-free products are further purified by crystallization from organic solvents, especially ethanol.
The compounds of general formula II are produced starting from the compounds 5-amino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxy-propyl)-monoamide or 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxy-propyl)-monoamide described in EP 308364 in CA 0221~38~ 1997-09-1 the way known to one skilled in the art (e.g.: Methoden der organischen Chemie [Methods of Organic Chemistry] (Houben-Weyl), Vol. E5, Carbonsauren und Carbonsaure Derivate [Carboxylic Acids and Carboxylic Acid Derivatives], Thieme Verlag, Stuttgart, New York, 1985).
For the production of especially preferred compounds with Z
meaning a chlorine atom, the reaction is performed, for example, in nonpolar to polar, preferably moderately polar, aprotic solvents with organic and/or inorganic acid halides, preferably acid chlorides. The reaction is performed at temperatures of between 0~C and 120~C, preferably at 50~ to 90~C. The reaction can be carried out in the presence or absence of basic catalysts such as pyridine or 4-dimethylaminopyridine.
The reaction preferably is performed in the presence of a basic catalyst in a slightly polar aprotic solvent, from which the acid chloride of general formula I precipitates as crystals and can be isolated easily and with good yield and purity.
Preferred solvents are ethyl acetate, isopropyl acetate, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, dimethylacetamide and dimethylformamide.
If 5-amino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxy-propyl)-monoamide is used as starting material, it can be reacted either first with acetoxyacetyl chloride and then with, e.g., the inorganic acid halide thionyl chloride to the intermediate 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxyacetoxypropyl)-amide-chloride or first with thionyl chloride and then with acetoxyacetyl chloride to the intermediate CA 022l~38~ l997-09-l~
5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-t2-oxo-1,3,2-dioxathiolan-4-ylmethyl)-amide-chloride.
The following examples are to explain the object of the invention, without intending that it be limited to these examples.
CA 0221~38~ 1997-09-1 ~xample 1: 5-Hydroxyacetylamino-2,4,6-triiodoisophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl~]-diamide ~.1. Production of acid chlorides 1.1.1. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride 200 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxy-propyl)-monoamide is suspended in 200 ml of dioxane, 114.4 g of acetoxyacetyl chloride is added, and the suspension is heated to 90~C. A solution develops. After about 2 hours, the TLC in, e.g., methylene chloride/methanol 10:3 shows that the amino group of the starting compound is quantitatively acylated.
49.84 g of thionyl chloride is added and stirred for another 2 hours at 90~C. The TLC in the above system then shows the quantitative reaction to acid chloride. The reaction solution is reduced by distillation in a vacuum to about one third of its volume, 350 ml of ethyl acetate is added, and it is stirred for 2 hours at room temperature. Ample crystallizate develops. The latter is filtered off, washed with ethyl acetate and dried in a vacuum at 50~C. The yield is 212 g = 91% of theory.
1.1.2. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride 71.6 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxy-propyl)-monoamide is suspended in 71.6 ml of ethyl CA 0221~38~ 1997-09-1 acetate, 34.71 g of acetoxyacetyl chloride is added, and the suspension is stirred for 4 hours at an internal temperature of about 82~C. Then, 23.8 g of thionyl chloride is added, and it is stirred for another 5 hours at about 85~C internal temperature.
The suspension is then diluted with 200 ml of ethyl acetate, cooled to room temperature, the crystallizate is filtered off, washed with ethyl acetate and dried in a vacuum at 50~C. Yield 75.5 g = 90.5% of theory.
1.1.3. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride 71.6 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxypropyl)-monoamide is suspended in 71.6 ml of ethyl acetate, 34.71 g of acetoxyacetyl chloride and 0.54 g of 4-dimethylaminopyridine (DMAP) is added, and the suspension is stirred for 2 hours at an internal temperature of about 82~C.
Then, 23.8 g of thionyl chloride is added, and it is stirred for another 5 hours at about 85~C internal temperature. The suspension is then diluted with 200 ml of ethyl acetate, cooled to room temperature, the crystallizate is filtered off, washed with ethyl acetate and dried in a vacuum at 50~C. Yield 71.8 g = 86~ of theory.
1.1.4. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride 71.6 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxy-propyl)-monoamide is suspended in 71.6 ml of diethylene CA 022l~38~ l997-09-l~
glycol dimethyl ether, 27.31 g of acetoxyacetyl chloride is added, and the suspension is stirred for 8 hours at an internal temperature of about 95~C. A solution develops. Then, 29.74 g of thionyl chloride is added, and it is stirred for another 2.5 hours at an internal temperature of about 83~C. The solution is then diluted with 200 ml of ethyl acetate, cooled to room temperature, the crystallizate is filtered off, washed with ethyl acetate and dried in a vacuum at 50~C. Yield 67.2 g = 80.5% of theory.
1.1.5. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono- -(2,3-diacetoxypropyl)-amide-chloride 357 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-diacetoxypropyl)-monoamide is refluxed in 1.6 l of dichloroethane with 178 ml of thionyl chloride for 1.5 hours. A solution develops from the suspension. The latter is cooled to room temperature and absorptively precipitated with saturated sodium bicarbonate solution until the aqueous phase reacts in a weakly alkaline manner. The phases are separated, the organic phase is concentrated by evaporation to oil, the oil is dissolved in of ethyl acetate, mixed with 204 g of acetoxyacetyl chloride and refluxed for about 8 hours. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride increasingly precipitates as crystals from the solution. It is cooled to room temperature, suctioned off, washed with ethyl acetate and dried in a vacuum at 50~C. The yield is 308 g =
72.3% of theory.
CA 0221~38~ 1997-09-1 1.1.6. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-(2-oxo-1,3,2-dioxathiolan-4-ylmethyl)-monoamide-chloride 119.08 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxy-propyl)-monoamide is suspended in 1070 ml of ethyl acetate, 85.44 g of thionyl chloride is added, and the suspension is heated to boiling. After about 20 minutes, a clear solution develops. 90 g of acetoxyacetyl chloride is added to this solution in the course of about 10 minutes and further stirred at boiling temperature. After about 4 hours, the product crystallizes out from the boiling reaction solution. After about 8 hours, the reaction is completed. It is cooled to room temperature, the crystallizate is filtered off, washed with ethyl acetate and dried at 50~C in a vacuum. Yield 97.86 g = 67.24% of theory.
1.1.7. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-(2-oxo-1,3,2-dioxathiolan-4-ylmethyl)-monoamide-chloride 63.1 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxypropyl)-monoamide is suspended in 120 ml of ethyl acetate, 12.5 g of thionyl chloride is gradually added at about 5-10~C and stirred for 3 hours at room temperature. The suspension is then heated to boiling, 41 g of acetoxyacetyl chloride is added in drops in the course of one hour, 0.6 g of 4-dimethylaminopyridine is added and refluxed for 3 hours. The suspension changes into a solution. After the end of this time, 23.8 g of thionyl chloride is added in drops to this solution in the course of 30 minutes and then refluxed for 2 hours. In this CA 0221~38~ 1997-09-1 time, the product increasingly precipitates as crystallizate from the solution. 200 ml of ethyl acetate is added, refluxed for another 30 minutes, then cooled to room temperature, the crystallizate is suctioned off, washed with ethyl acetate and dried for 24 hours at 50~C in a vacuum. Yield: 58.5 g = 73 . 5%
of theory.
1.1.8. 5-Acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxyacetoxypropyl)-amide-chloride 63.1 g of 5-amino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxypropyl)-monoamide is suspended in 100 ml of ethyl acetate, 60.4 g of acetoxyacetyl chloride and 1 g of 4-dimethylaminopyridine are added, and the suspension is refluxed.
The suspension gradually changes into a solution. After about 4 hours, the acylation is complete. 14. 7 ml of thionyl chloride is added and refluxed for another 5 hours. The product begins to precipitate as crystals. To increase the crystallizate, another 200 ml of ethyl acetate is added, cooled to room temperature and stirred for 2 more hours. The crystallizate is suctioned off, washed with ethyl acetate and dried at 50~C in a vacuum.
Yield: 64.8 g = 68.2~ of theory CA 0221~38~ 1997-09-1 1.2. Production of 5-hydroxyacetylamino-2,4,6-triiodoisophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide 1.2.1. 500 g of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride (Example 1.1.1) is suspended in 1300 ml of acetone, 69.2 g of N-methylaminopropanediol and 188.55 g of Na2C03 x 10 H20 are added, and the suspension is refluxed for 1 hour. The inorganic salts are filtered off, and the filtrate is mixed at 50~C in the course of about 1 hour with a total of 100 ml of 50% by weight of sodium hydroxide solution. The solution is then brought to pH 7 with 27 ml of 11.5N hydrochloric acid, desalinated on ion exchangers, the aqueous eluate is concentrated by evaporation in a vacuum to an oil, and the latter crystallizes from 2 l of ethanol in boiling heat.
Yield: 295.6 g = 63.5% of theory 1.2.2. 90 g of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxypropyl)-amide-chloride (Example 1.1.2) was dissolved in 260 ml of dioxane, 47.3 g of Na2C03 x 10 H20 and 13.86 g of N-methylaminopropanediol were added and stirred for 3 hours at room temperature. The inorganic salts were suctioned off, the filtrate was concentrated by evaporation in a vacuum to an oil, this oil was dissolved in 200 ml of water and mixed at 40~C gradually with 35 ml of 50% by weight of sodium hydroxide solution. The aqueous solution was then brought to pH
CA 0221~38~ 1997-09-1 7 with about 6 ml of 11.5N hydrochloric acid, desalinated on ion exchangers, the aqueous eluate was concentrated by evaporation in a vacuum to an oil, and the latter was crystallized from 350 ml of ethanol in boiling heat. Yield: 58.1 g = 68% of theory 1.2.3. 100 g of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-(2-oxo-1,3,2-dioxathiolan-4-ylmethyl)-monoamide-chloride (Example 1.1.7) is suspended in 500 ml of acetone, 39.5 g of soda decahydrate and 14.5 g of methylaminopropanediol are added and refluxed for 1 hour. It is then cooled to room temperature, the inorganic salts are filtered off, the filtrate is largely concentrated by evaporation under reduced pressure, and the residue is dissolved in 300 ml of water. At 40~C, the aqueous solution is gradually mixed with about 20 ml of 50% by weight of NaOH and in this case the pH is held between 10 and 12. The basic solution is then desalinated on a cation exchanger and an anion exchanger, the aqueous eluate is concentrated by evaporation to an oil, and the latter is crystallized from about 300 ml of ethanol. Yield: 61.5 g = 63% of theory Example 2: 5-Hydroxyacetylamino-2,4,6-triiodoisophthalic acid-(2,3-dihydroxypropyl)-[N-bis(2-hydroxyethyl)]-diamide 2.1. 100 g of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-(2-oxo-1,3,2-dioxathiolan-4-ylmethyl)-monoamide-chloride (Example 1.1.7) is suspended in 500 ml of acetone, 39.5 g of soda decahydrate and 14.5 g of diethanolamine are added and refluxed CA 0221~38~ 1997-09-1 for 1 hour. It is then cooled to room temperature, the inorganic salts are filtered off, the filtrate is largely concentrated by evaporation under reduced pressure, and the residue is dissolved in 300 ml of water. At 40~C, the aqueous solution is gradually mixed with about 20 ml of 50% by weight of NaOH and in this case, the pH is held between 10 and 12. The basic solution is then desalinated on a cation exchanger and an anion exchanger, the aqueous eluate is concentrated by evaporation to an oil, and the latter is crystallized from about 300 ml of ethanol. Yield:
68.6 g = 70.3% of theory 2.2. 95 g of 5-acetoxyacetylamino-2,4,6-triiodoisophthalic acid-mono-(2,3-diacetoxyacetoxypropyl)-amide-chloride (Example 1.1.8) is suspended in 500 ml of acetone, 31.5 g of soda decahydrate and 11.6 g of diethanolamine are added and refluxed for 1 hour. It is then cooled to room temperature, the inorganic salts are filtered off, the filtrate is largely concentrated by evaporation under reduced pressure, and the residue is dissolved in 300 ml of water. At 40~C, the aqueous solution is gradually mixed with about 16 ml of 50% by weight of NaOH, and in this case, the pH is held between 10 and 12. The basic solution is then desalinated on a cation exchanger and an anion exchanger, the aqueous eluate is concentrated by evaporation to an oil, and the latter is crystallized from about 300 ml of ethanol. Yield:
51 g = 65.7% of theory.
CA 0221~38~ 1997-09-1 Example 3: Solution for injection for computer tomography 683.7 g of the anhydrous and pyrogen-free substance according to Example 1 is added to 500 ml of pyrogen-free water containing 10 mmol of tris(tris-hydroxymethylaminomethane) and 100 mg of Na2Ca EDTA, dissolved in heat, cooled, adjusted to pH
6.8 with lN HCl and filled with pyrogen-free water to 1000 ml.
The solution is bottled in portions of 200 ml in glass flasks holding 250 ml, which are tightly sealed with rubber stoppers, flanged and heat-sterilized for 20 minutes at 121~C.
Example 4: Use in computer tomography The product according to Example 3 is intravenously injected in patients at a dose of 2 ml/kg at an injection rate of 4 ml/sec. 25 seconds after the beginning of the injection, the area of the liver is scanned from cranial to caudal with a layer thickness of 0.5 cm and a table feed rate of 0.7 cm/sec for a period of 30 seconds in the case of respiratory arrest with a spiral CT. A visualization of the abdomen in the area of the liver develops in 30 layers, in which areas well supplied with blood show a high radiation absorption. In this way, certain diseases of the liver can be revealed significantly better than without contrast media.
Example 5: Use in computer tomography 30 ml of the product according to Example 3 is diluted with 970 ml of drinking water. The solution is drunk slowly within 1 hour before a study of the abdomen with the aid of computer tomography. Stomach and intestines can be better defined by the contrast medium in computer tomography.
Claims (16)
1. Compounds of general formula I
(I) in which either - R1 stands for the methyl radical and R2 stands for the 2,3-dihydroxypropyl radical or - R1 and R2 in each case stand for the 2-hydroxyethyl radical.
(I) in which either - R1 stands for the methyl radical and R2 stands for the 2,3-dihydroxypropyl radical or - R1 and R2 in each case stand for the 2-hydroxyethyl radical.
2. Process for the production of compounds of general formula I, characterized in that a compound of general formula II
(II), in which X1, X2 and X3 stand for hydroxy protective groups and Z stands for a reactive acid or ester radical, is reacted in a polar solvent or a solvent mixture, containing at least one polar solvent, at a temperature of 0°C to 120°C, optionally in the presence of an auxiliary base with diethanolamine or N-methylaminopropanediol and then the hydroxy protective groups are cleaved off in a known way.
(II), in which X1, X2 and X3 stand for hydroxy protective groups and Z stands for a reactive acid or ester radical, is reacted in a polar solvent or a solvent mixture, containing at least one polar solvent, at a temperature of 0°C to 120°C, optionally in the presence of an auxiliary base with diethanolamine or N-methylaminopropanediol and then the hydroxy protective groups are cleaved off in a known way.
3. Process for the production of compounds of general formula I, wherein a compound of general formula III
(III), in which X1, X2 and X3 stand for hydroxy protective groups is reacted in a polar solvent or a solvent mixture, containing at least one polar solvent, at a temperature of 0°C to 120°C, in the presence of an auxiliary base with diethanolamine or N-methylaminopropanediol and then the hydroxy protective groups are cleaved off in a known way.
(III), in which X1, X2 and X3 stand for hydroxy protective groups is reacted in a polar solvent or a solvent mixture, containing at least one polar solvent, at a temperature of 0°C to 120°C, in the presence of an auxiliary base with diethanolamine or N-methylaminopropanediol and then the hydroxy protective groups are cleaved off in a known way.
4. Process according to claim 2 or 3, wherein at least one of groups X1, X2 or X3 stands for an acetyl radical or an acetoxyacetyl radical.
5. Process according to claim 2 or 3, wherein X2 and X3 together stand for a radical of formula - or
6. Process according to claim 2 or 3, wherein the auxiliary base is triethylamine, tributylamine, sodium carbonate or potassium carbonate.
7. Process according to claim 2 or 3, wherein acetone, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, dimethylacetamide or dimethylformamide or mixtures of these solvents are used as solvent.
8. Process according to claim 2 or 3, wherein the reaction is performed in the presence of water.
9. Pharmaceutical agent, containing at least one compound of general formula I.
10. Pharmaceutical agent according to claim 9, containing at least one compound of general formula I together with a calcium complex of the ethylenediaminepentaacetic acid.
11. Pharmaceutical agent according to claim 9, containing at least one compound of general formula I together with vasodilators and/or anticoagulants.
12. Use of the compounds of general formula I for the production of x-ray contrast media.
13. Use of compounds of general formula I according to claim 12 for the production of x-ray contrast media for computer tomography.
14. Use of the compounds of general formula I according to claim 12 for the production of x-ray contrast media for urography, myelography and/or interventional radiology.
15. Use of the compounds of general formula I according to claims 12 and 13 for the production of x-ray contrast media the interventional radiology with the aid of computer tomography.
16. Use of the compounds of general formula I according to claim 12 for the production of x-ray contrast media for diagnostic visualization of the gastrointestinal tract and/or of the liver.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19510864.7 | 1995-03-16 | ||
| DE19510864A DE19510864A1 (en) | 1995-03-16 | 1995-03-16 | X-ray contrast media for computed tomography and urography |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2215385A1 true CA2215385A1 (en) | 1996-09-19 |
Family
ID=7757670
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002215385A Abandoned CA2215385A1 (en) | 1995-03-16 | 1996-02-21 | X-ray contrast media for computer tomography and urography |
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| Country | Link |
|---|---|
| EP (1) | EP0815072B1 (en) |
| JP (1) | JPH11501638A (en) |
| KR (1) | KR19980703059A (en) |
| AT (1) | ATE194138T1 (en) |
| AU (1) | AU4718696A (en) |
| CA (1) | CA2215385A1 (en) |
| CZ (1) | CZ291597A3 (en) |
| DE (2) | DE19510864A1 (en) |
| DK (1) | DK0815072T3 (en) |
| ES (1) | ES2148731T3 (en) |
| FI (1) | FI973692A0 (en) |
| GR (1) | GR3034472T3 (en) |
| HU (1) | HUP9800850A3 (en) |
| IL (1) | IL117373A0 (en) |
| NO (1) | NO974259L (en) |
| PL (1) | PL322200A1 (en) |
| PT (1) | PT815072E (en) |
| SK (1) | SK121797A3 (en) |
| WO (1) | WO1996028415A1 (en) |
| ZA (1) | ZA962142B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19731591C2 (en) * | 1997-07-17 | 1999-09-16 | Schering Ag | Pharmaceutical compositions containing triiodoaromatics containing perfluoroalkyl groups and their use in tumor therapy and interventional radiology |
| DE19740403C2 (en) * | 1997-09-09 | 1999-11-11 | Schering Ag | New contrast media |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1548594A (en) * | 1976-06-11 | 1979-07-18 | Nyegaard & Co As | Triiodoisophthalic acid amides |
| DE2909439A1 (en) * | 1979-03-08 | 1980-09-18 | Schering Ag | NEW NON-ionic x-ray contrast agents |
| IT1193211B (en) * | 1979-08-09 | 1988-06-15 | Bracco Ind Chimica Spa | 2,4,6-TRIIODE-ISOPHTHALIC ACID DERIVATIVES, METHOD FOR THEIR PREPARATION AND CONTRAST MEANS THAT CONTAIN THEM |
| DE3937118A1 (en) * | 1989-11-03 | 1991-05-08 | Schering Ag | NON-ionic x-ray contrast agents with high iodine content |
| US5075502A (en) * | 1989-12-13 | 1991-12-24 | Mallinckrodt, Inc. | Nonionic x-ray contrast agents, compositions and methods |
| WO1993010078A1 (en) * | 1991-11-18 | 1993-05-27 | Centro Investigacion Justesa Imagen S.A. | New non ionic iodized agents for x-ray contrasting method for preparing them and galenical compositions containing them |
| CA2124559A1 (en) * | 1991-12-03 | 1993-06-10 | Mills Thomas Kneller | Nonionic x-ray contrast agents, compositions and methods |
| AU5093993A (en) * | 1992-09-02 | 1994-03-29 | Mallinckrodt Medical, Inc. | Nonionic X-ray contrast agents compositions and methods |
-
1995
- 1995-03-16 DE DE19510864A patent/DE19510864A1/en not_active Withdrawn
-
1996
- 1996-02-21 SK SK1217-97A patent/SK121797A3/en unknown
- 1996-02-21 CA CA002215385A patent/CA2215385A1/en not_active Abandoned
- 1996-02-21 WO PCT/EP1996/000735 patent/WO1996028415A1/en not_active Application Discontinuation
- 1996-02-21 JP JP8527203A patent/JPH11501638A/en active Pending
- 1996-02-21 ES ES96902993T patent/ES2148731T3/en not_active Expired - Lifetime
- 1996-02-21 HU HU9800850A patent/HUP9800850A3/en unknown
- 1996-02-21 PT PT96902993T patent/PT815072E/en unknown
- 1996-02-21 AT AT96902993T patent/ATE194138T1/en not_active IP Right Cessation
- 1996-02-21 KR KR1019970706468A patent/KR19980703059A/en not_active Application Discontinuation
- 1996-02-21 DK DK96902993T patent/DK0815072T3/en active
- 1996-02-21 CZ CZ972915A patent/CZ291597A3/en unknown
- 1996-02-21 EP EP96902993A patent/EP0815072B1/en not_active Expired - Lifetime
- 1996-02-21 AU AU47186/96A patent/AU4718696A/en not_active Abandoned
- 1996-02-21 PL PL96322200A patent/PL322200A1/en unknown
- 1996-02-21 DE DE59605508T patent/DE59605508D1/en not_active Expired - Lifetime
- 1996-03-05 IL IL11737396A patent/IL117373A0/en unknown
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1997
- 1997-09-15 NO NO974259A patent/NO974259L/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| ES2148731T3 (en) | 2000-10-16 |
| FI973692A (en) | 1997-09-15 |
| IL117373A0 (en) | 1996-07-23 |
| FI973692A0 (en) | 1997-09-15 |
| EP0815072A1 (en) | 1998-01-07 |
| DK0815072T3 (en) | 2000-09-04 |
| HUP9800850A2 (en) | 1998-07-28 |
| CZ291597A3 (en) | 1998-02-18 |
| DE19510864A1 (en) | 1996-09-19 |
| SK121797A3 (en) | 1998-05-06 |
| KR19980703059A (en) | 1998-09-05 |
| MX9706555A (en) | 1997-11-29 |
| PL322200A1 (en) | 1998-01-19 |
| EP0815072B1 (en) | 2000-06-28 |
| AU4718696A (en) | 1996-10-02 |
| ATE194138T1 (en) | 2000-07-15 |
| ZA962142B (en) | 1996-09-26 |
| GR3034472T3 (en) | 2000-12-29 |
| PT815072E (en) | 2000-10-31 |
| WO1996028415A1 (en) | 1996-09-19 |
| JPH11501638A (en) | 1999-02-09 |
| DE59605508D1 (en) | 2000-08-03 |
| HUP9800850A3 (en) | 1998-08-28 |
| NO974259L (en) | 1997-11-14 |
| NO974259D0 (en) | 1997-09-15 |
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