DE4446694A1 - Using additives to contrast agents to improve imaging - Google Patents

Abstract

The invention concerns the use of prostacycline derivatives and the use of urea in order to improve imaging in X-ray, ultrasound, nuclear or MRI diagnostics.

Description

Contrast agents are indispensable aids in X-ray, Magnetic resonance, nuclear or ultrasound diagnostics for general Improvement of the imaging, for the more specific representation of individual Organs or tissues or to visualize "dynamic" processes or pathological conditions. Summarizing representations are in the Literature described.

In X-ray diagnostics, the imaging is based on the different Absorption of the irradiated tissue or on the absorption of the X-rays through the contrast medium. All administered parenterally X-ray contrast agents use iodine as a radiation absorbing element and the substances currently available contain either three or six Iodine atoms per molecule in order to achieve the highest possible contrast. All Contrast agents are derivatives of trÿodbenzene either as monomers Compounds (three iodine atoms) or - connected by a bridge - as dimers Derivatives (six iodine atoms). Additional substituents increase the hydrophilicity and improve tolerance.

After intravenous or intra-arterial injection of the X-ray contrast media these compounds are distributed very quickly in the extracellular space and become then excreted through the kidneys by glomerular filtration.

The search for contrast media for X-ray diagnostics started immediately after the X-rays were discovered by W.C. X-ray in 1895. The goals and the hoped-for properties for these contrast agents have changed  not changed significantly since then. We are looking for well tolerated Substances with high radiation-absorbing potential. With the introduction however, there is apparently a limit in of three or six iodine atoms per molecule the radiation absorption has been achieved, which is currently despite the most intense Efforts cannot be exceeded.

As a way out, various research groups tried to find the Imaging especially of the blood vessels through the addition of pharmacological to improve active substances to the tri or hexajod compounds. At the Papaverine was the most intensively examined. It could be shown, that by adding papaverine to X-ray contrast media, imaging of Vessels improved or that the combination of X-ray contrast agents with Papaverine even for the differential diagnosis of myocardial Reduced blood flow can be used (Cheirif et al. J. Am. Coll. Cardiol. 11: 735-743, [1988]; Hodgson and Williams, Am. Heart J. 114: 704-10 [1987]). However, it soon became apparent that precipitations in the Mixing the contrast agent with the papaverine can come to that Thrombosis and even death (Irving and Burbridge, Radiology 173: 91-2 [1989]; Shah and Gerlock, Radiology 162: 619-20 [1987]; Pallan et al., Proc. West. Pharmacol. Soc. 34: 315-7 [1991]; Burbridge, Radiology 189: 287 [1993]; Delcour, Am. J. Roentgenol. 147: 1096 [1986]; McGill et al., Radiology 166: 577-8 [1988]; Pilla et al., Am. J. Roentgenol. 146: 1300-1 [1986]). This initially only for ionic contrast media such as amidotrizoate or ioxaglate reported intolerances were later also for non-ionic compounds such as iopamidol found (Pallan et al., Radiology 187: 257-9 [1993]), so that the addition of papaverine is severely restricted has been.

When looking for alternatives, other vasodilators such as Dipyramidol and tolazoline tested for their effectiveness. Especially on Hearts were hereby able to achieve improvements in imaging (Johnston et al. J. Nucl. Med. 28: 871-7 [1987]; Burgener and Gutierrez; Invest. Radiol. 20: 399-402 [1985]). However, again very soon Solubility problems have been reported (Zagoria et al., Invest. Radiol. 22: 513-4 [1987]).

It is therefore very desirable to be well tolerated and not compatible with others Miscibility problems with additives to find contrast agents that can improve imaging.  

It has now been found that, surprisingly, prostaglandin derivatives, especially prostacyclins, when administered shortly before or after a dose of X-ray, ultrasound, nuclear or MRI contrast media or at simultaneous administration are capable of imaging in the vessels but also to improve significantly in the kidney and urinary tract and that Urea also meets this requirement.

The present invention relates to the use of a prostaglandin derivatives or the corresponding cyclodextrin clathrates and Urea to improve the imaging of contrast media in the X-ray, MRI, ultrasound or nuclear diagnostics.

The invention preferably relates to the use of urea and / or one or several prostacyclin derivatives of the general formula

wherein
R¹ is hydrogen or a C₁-C₄ alkyl radical,
n = 0 to 3,
X, Y independently of one another are a —CH₂ group or an oxygen atom,
Z is hydrogen, fluorine or CN,
A is a trans -CH = CH- or a -C≡C group,
W is a free or functionally modified hydroxymethyl group on the hydroxyl group, where the hydroxyl group can be α- or β-permanent,
D is a straight-chain or branched C₁-C₅ alkylene group,
E is a -C≡C group,
R² is a C₁-C₂ alkyl group,
R³ is a free or functionally modified hydroxy group, and if R¹ is hydrogen, their salts with physiologically compatible bases ₁ and their α-, β- or γ-cyclodextrin clathrates or Ataprost, Beraprost, Ciprosten, CS 570, FCE 22509, Naxaprosten, RS 93427, SC 39902 or Taprosten to improve the imaging when using X-ray, ultrasound, nuclear or NMR contrast media.

The present invention particularly preferably relates to the use of the Prostacyclin derivatives iloprost, iloprost clathrate, cicaprost, cicaprost clathrate, Eptaloprost or eptaloprost clathrate.

As alkyl groups in R¹ are straight or branched chain alkyl groups with 1-4 Consider carbon atoms such as methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, tert-butyl. The alkyl groups R 1 can optionally be substituted by halogen atoms, methoxy, ethoxy, phenyl or (C₁-C₂) dialkylamines.

Examples of substituents are fluorine, chlorine or Bromine atoms, phenyl, dimethylamine, diethylamine, methoxy or ethoxy. Preferred alkyl groups R1 are methyl, ethyl, dimethylaminopropyl.

Methyl and ethyl may be mentioned as the alkyl group R.sup.2.

The hydroxyl groups in R³ and W can exist as free hydroxyl groups, the hydroxyl group in W is preferably α-permanent, or functional can be modified, for example by etherification or esterification. Free hydroxy groups are preferred.  

The radicals known to the person skilled in the art come in as ether or acyl radicals Consideration. Easily cleavable ether residues such as, for example, are preferred Tetrahydropyranyl, tetrahydrofuranyl, α-ethoxyethyl, trimethylsilyl, dimethyl tert-butylsilyl, diphenyl-tert.-butylsilyl or tribenzylsilyl.

Acyl radicals which may be mentioned are, for example, acetyl, propionyl, or butyryl Benzoyl.

Straight-chain or branched saturated ones come as alkylene group D. Alkyl groups with 1-5 C atoms, for example methylene, ethylene, 1- or 2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1-methyldimethylene, 1-methyltrimethylene, 1-methyltetramethylene.

To bind salt with the free acids (R¹ = H) are inorganic and suitable organic bases, as the person skilled in the art for forming physiologically compatible salts are known. Examples include: Alkali hydroxides such as lithium, sodium or potassium hydroxide, alkaline earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, Triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, Glucosamine, lysine, ornithine, arginine, etc.

The clathrates with α-, β- or γ-cyclodextrin are analogous to the regulation WO 87105 294 obtained. Preferred clathrates are those with β-cyclodextrin.

The preparation of the compounds of the formula I is described in detail in EP 2 234 B1 and EP 11 591 B1.

EP 11 591 B1 describes the following for prostacyclin derivatives of the formula I. pharmacological properties described:

Reduction in peripheral arterial and coronary vascular resistance, Inhibition of platelet aggregation and induction of Platelet thrombi, myocardial cytoprotection and thus lowering the systemic blood pressure without stroke volume and coronary at the same time Lower blood flow; Treatment of stroke, prophylaxis and Therapy of coronary thrombosis, heart attack, peripheral Arterial diseases, arteriosclerosis and thrombosis,  Therapy of shock, inhibition of gastric acid secretion and Cytoprotection of the gastric and intestinal mucosa; anti-allergic Properties, lowering pulmonary vascular resistance and pulmonary blood pressure, use instead of heparin or adjuvant dialysis or hemofiltration, preservation of blood plasma, especially from preserved platelets, inhibition of labor pains, Treatment of pregnancy toxicosis, increase in cerebral Blood circulation etc. In addition, the new prostaglandin analogues antiproliferative properties.

EP 86 404 B1 describes the use of carbacyclins for prophylaxis and Therapy of ischemic attacks of the CNS system, for cytoprotection in the Liver and in the pancreas as well as the combination with β-blockers or diuretics described. WO 86/00 808 A1 = DE 34 27 797 C2 describes cytoprotection the kidney and the suitability of the prostacyclin derivatives of the formula I for Treatment of organs to be transplanted. In DE 35 26 362 A1 the combination of the prostacyclin derivatives of the formula I with Thromboxane antagonists for use in thrombotic or thromboemobolic clinical pictures.

DE 35 44 663 A1 describes the combination of the prostacyclin derivatives of the formula I. with fibrinolytics to prevent rethrombosis after thrombosis known.

DE 36 08 088 describes the clathrates of the carbacyclin derivatives of the formula I. described. DE 36 31 169 A1 in addition to those in EP 11 591 B1 described administration forms the topical administration form known.

DE 41 35 193 C1 describes the use of the above compounds as Additive to avoid or treat microcirculation disorders described after administration of X-ray, ultrasound or MRI contrast media.  

The use of the claimed within the scope of this invention Prostacyclin derivatives of formula I is not in any of the foregoing Disclosures or patents. Completely surprising Studies on the animal model showed that the compounds mentioned in improving imaging through x-ray, ultrasound, nuclear or have MRI contrast agent successfully used. Of the Concentration range of the contrast agents added Prostacyclin derivatives is preferably 0.1-100 ng / ml. In this Concentration range already occurs an improvement in imaging without administration of contrast media, especially in MRI diagnostics and of angiography.

The use of urea to improve imaging is in none Disclosure and no patent described. The only Investigation that has been reported in the literature relates to the Change in diuresis after adding sodium iodide by adding Urea (A. Roseno, Klin. Wochenschr. 25: 1165-70 [1929]). This work primarily aimed at faster excretion and thus faster detoxification of highly toxic compared to today's X-ray contrast media Sodium iodide.

It has now been found that the addition of urea to today's X-ray contrast media is surprisingly capable of imaging improve in the urogram, although urea leads to a strong osmodeuresis and thus leads to dilution of the excreted contrast medium. The less concentrated contrast medium in the urine should actually be a worse one Effect image quality. Correspondingly unfavorable findings are Obtained addition of mannitol to a nonionic contrast medium (I. Lovelt et al., in Recent Developments in Nonionic Contrast Media, V. Taenzer, S. Turn: progress Röntgenstr. Suppl. 128: 105-7 [1989]). Of the Concentration range of the urea added to the contrast media lies preferably at 10-150 mg / ml. One occurs in this concentration range Imaging also improved without the addition of contrast media on, especially in MRI diagnostics and angiography.

Examples

The following examples serve to explain the invention in more detail object without wishing to restrict it to them.

1. Addition of Iloprost to Ultravist: imaging of vessels

A rabbit with a body weight of approx. 3 kg received an injection of the non-ionic, low-osmolar X-ray contrast agent Ultravis®-300 (active ingredient: Iopromide) into the common carotid artery. The dose was 2 ml / kg, the injection rate was 1-1.5 ml / sec. An angiogram was taken immediately afterwards ( Fig. 1).

After a resting phase, the examination was repeated, this time adding 10 ng / ml iloprost to the contrast medium. The result is shown in Fig. 2.

After another rest period, the examination was repeated carried out. However, this time the injection consisted of Ultravis® 300 without iloprost additive.

Result

The addition of 10 ng / ml Iloprost to Ultravist®-300 improved this Angiogram extremely strong. Another injection of Ultravist®-300 showed the original - less pronounced - angiogram.  

2. Addition of Iloprost to Ultravist: use in urography

A rabbit of approx. 3 kg body weight received an intravenous injection of the non-ionic, low-osmolar X-ray contrast agent Ultravist®-370 (active ingredient: iopromide). The dose was 2 ml / kg, the injection rate was 1-1.5 ml / sec. A urogram was recorded immediately afterwards ( Fig. 3).

After a resting phase, the examination was repeated, this time adding 10 ng / ml lloprost to the contrast medium. The result is shown in Fig. 4.

After another rest period, the examination was repeated carried out. However, this time the injection consisted of Ultravis® 370 without iloprost additive.

Result

The addition of 10 ng / ml Iloprost to Ultravist®-370 improved this Urogram clearly.

3. Addition of urea to Isovist: use in urography

The investigation was designed as a block test. In the first block 3 animals each with Isovist®-280 (active ingredient Iotrolan) and 3 animals with Isovist®-280 + 52 mg urea / ml treated. In the second block - 3 days later - the Animals administered the other formulation.

Result

The addition of 52 mg of urea to each 1 ml of Isovist®-280 significantly improved the urogram ( Figs. 5 and 6), especially the kidney cups are more contrasted.

Claims (11)

1. Use of a prostacyclin derivative or the corresponding β-cyclodextrin clathrates to improve imaging in the X-ray, ultrasound, nuclear or MRI diagnostics. 2. Use of a prostacyclin derivative or the corresponding β-cyclodextrin clathrates to improve imaging in the X-ray, ultrasound, nuclear or MRI diagnostics in combination with a contrast medium. 3. Use of the prostacyclin derivatives of the general formula I wherein
R¹ is hydrogen or a C₁-C₄ alkyl radical,
n = 0 to 3,
X, Y independently of one another are a —CH₂ group or an oxygen atom,
Z is hydrogen, fluorine or CN,
A is a trans -CH = CH or a -C≡C group,
W is a free or functionally modified hydroxymethyl group on the hydroxyl group, where the hydroxyl group can be α- or β-permanent,
D is a straight-chain or branched C₁-C₅ alkylene group,
E is a -C≡C group,
R² is a C₁-C₂ alkyl group,
R³ is a free or functionally modified hydroxy group, and if R¹ is hydrogen, their salts with physiologically compatible bases, and their α, β- or γ-cyclodextrin clathrates or Ataprost, Beraprost, Ciprosten, CS 570, FCE 22509, Naxaprosten, RS 93427, SC 399902 or taprosten to improve the imaging when using X-ray, ultrasound, nuclear or MRI contrast media according to claim 1 or 2. 4. Use of iloprost or iloprost clathrate according to claim 1 or 2. 5. Use of cicaprost or cicaprost clathrate according to claim 1 or 2. 6. Use of eptaloprost or eptaloprost clathrate according to claim 1 or 2. 7. Use of 5 - [(E) - (1S, 5S, 6S, 7R) -7-hydroxy-6 - [(3S, 4S)] - 3-hydroxy-4- methyl-1,6-nona-diynyl] bicyclo [3.3.0] oct-3-ylidene] pentanoic acid or the corresponding clathrate according to claim 1 or 2. 8. Use of 5 - [(E) - (1S, 5S, 6S, 7R) -7-Hydroxy6- [3S, 4S) -3-hydroxy-4- methyl-1,6-nona-diynyl] bicyclo [3.3.0] oct-3-ylidene] -5-fluoro-3- oxapentanoic acid or the corresponding clathrate according to claim 1 or 2. 9. Use of urea to improve imaging in the X-ray, ultrasound, nuclear or MRI diagnostics. 10. Use of urea to improve imaging in the X-ray, ultrasound, nuclear or MRI diagnostics in combination with a contrast medium. 11. Use of a prostacyclin derivative according to claim 1 or 2 together with urea according to claim 9 or 10 to improve the Imaging in X-ray, ultrasound, nuclear or MRI diagnostics.