WO1996017629A1

WO1996017629A1 - Use of additives in contrast mediums to improve imaging

Info

Publication number: WO1996017629A1
Application number: PCT/EP1995/004826
Authority: WO
Inventors: Werner Krause; Ulrich Speck; Wolf-Rüdiger Press
Original assignee: Schering Aktiengesellschaft
Priority date: 1994-12-09
Filing date: 1995-12-08
Publication date: 1996-06-13
Also published as: CA2207025A1; EP0789594A1; NO972613D0; NO972613L; JPH10509691A; DE4446694A1

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

Using additives to contrast agents to improve imaging

The invention relates to the use of prostacyclins and urea as an additive to contrast agents to improve imaging.

description

Contrast agents are indispensable aids in X-ray, magnetic resonance, nuclear or ultrasound diagnostics for general improvement of imaging, for more specific imaging of individual organs or tissues or for the visualization of "dynamic" processes or pathological conditions. Summary representations are described in the literature.

In X-ray diagnostics, imaging is based on the different absorption of the irradiated tissue or on the absorption of the X-ray radiation by the contrast medium. All parenterally administered X-ray contrast media 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 commercially available X-ray contrast media are derivatives of triiodobenzene. It these are either monomeric compounds with three iodine atoms or dimeric derivatives with six iodine atoms, which have two triiodobenzene derivatives connected by a bridge. Additional substituents increase the hydrophilicity and improve the tolerance.

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

The search for contrast media for X-ray diagnostics began immediately after the discovery of X-rays by W.C. Röntgen in 1895. The goals and the hoped-for properties for these contrast agents have not changed significantly since then. We are looking for well-tolerated substances with a high radiation-absorbing potential. With the introduction of three or six iodine atoms per molecule, however, a limit in radiation absorption has apparently been reached which, despite intensive efforts, cannot be exceeded at the moment.

As a way out, various research groups therefore tried to improve the imaging, especially of the blood vessels, by adding pharmacologically active substances to the tri or hexajod compounds. Papaverine was the most intensively examined. It could be shown that the addition of papaverine to X-ray contrast media improves the imaging of vessels or that the combination of X-ray contrast media with papaverine can even be used for the differential diagnosis of myocardial poor blood circulation (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 there could be precipitates in the contrast agent and papaverine mixture that could lead to 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]). These incompatibilities, which were initially only reported for ionic contrast media such as amidotrizoate or loxaglate, were later found for nonionic compounds such as lopamidol (Pallan et al., Radiology 187: 257-9 [1993]), so that the addition of papaverine was severely restricted. When looking for alternatives, other vasodilators such as dipyramidol and tolazoline were examined for their effectiveness. Improvements in imaging could be achieved especially at the heart (Johnston et al. J. Nucl. Med. 28: 871-7 [1987]; Burgener and Gutierrez; Invest. Radiol. 20: 399-402 [1985]). However, solubility problems were reported again very soon (Zagoria et al., Invest. Radiol. 22: 513-4 [1987]).

It is therefore very desirable to find other well-tolerated and non-miscible additives to contrast agents that can improve imaging.

It is therefore an object to provide such additives for contrast agents.

This object has been achieved by the present invention.

It has now been found that, surprisingly, the addition of prostaglandin derivatives to contrast media is capable of significantly improving imaging in the vessels but also in the kidney and urinary tract and that urea also meets this requirement.

Contrast media in this sense are X-ray, MRI or ultrasound contrast media and nuclear diagnostics.

The present invention therefore relates to the subject matter characterized in the claims, namely the use of prostaglandin derivatives and urea to improve the imaging of contrast media in X-ray, MRI, ultrasound or nuclear diagnostics. Cyclodextrin clathrates of prostaglandins are also to be understood as prostaglandin derivatives.

Examples of prostaglandin derivatives which are suitable for this use include Ataprost (INN), Beraprost (INN), Ciprosten (INN), CS 570 (INN), FCE 22509 (INN), Naxaprosten (INN), RS 93427 ( INN), SC 39902 (INN), taprostening (INN), 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 and 5 - [(E) - (1 S, 5S, 6S, 7R) -7-hydroxy- 6- [3S, 4S) -3-hydroxy-4-methyl-1, 6-nonadiinyl] bicyclo [3.3.0] oct-3-ylidene] -5-fluoro-3-oxapentanoic acid. The invention preferably relates to the use of urea and / or one or more prostacyclin derivatives of the general formula (I)

wherein

R ^{1 represents} hydrogen or a C ₈ -C ₈ alkyl radical, n represents the numbers 0 to 3,

X, Y independently of one another represent a -CH ₂ group or an oxygen atom,

Z represents hydrogen, fluorine or CN, A represents a transient -CH = CH- or a -CsC group,

W for a free or functionally modified on the hydroxy group

Hydroxymethyl group, where the hydroxyl group can be α or β,

D represents a straight-chain or branched C 1 -C ₅ alkylene group, E represents a -CsC group,

R ^{2 represents} a C ₁ -C ₂ alkyl group,

R ^{3 stands} for a free or functionally modified hydroxy group, as well as their cyclodextrin clathrates, and - if R ^{1 is} hydrogen - their salts with physiologically compatible bases, to improve imaging when using X-ray, ultrasound, nuclear or NMR Contrast agents. The present invention particularly preferably relates to the use of the prostacyclin derivatives lloprost, iloprost clathrate, cicaprost, cicaprost clathrate, eptaloprost or eptaloprost clathrate.

The alkyl groups in R ¹ are straight or branched chain alkyl groups with 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. -Butyl. The alkyl groups R ¹ can optionally be substituted by fluorine, chlorine, bromine or iodine atoms, methoxy, ethoxy, phenyl or (-C-C ₂ ) dialkylamino groups, such as dimethylamine or diethylamine. Preferred alkyl groups R ¹ are methyl, ethyl and dimethylaminopropyl.

R ² can represent a methyl or an ethyl radical.

The hydroxyl groups in R ³ and W can be present as free hydroxyl groups, the hydroxyl group in W preferably being α-permanent, or can be functionally modified, for example by etherification or esterification. Free hydroxy groups are preferred.

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

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

Suitable alkylene groups D are straight-chain or branched saturated alkyl groups having 1 to 5 carbon atoms, for example methylene, ethylene, 1-propylene, 2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1-methyldimethylene, 1-methyltrimethylene, 1-methyltetramethylene.

Inorganic and organic bases, as are known to the person skilled in the art for the formation of physiologically compatible salts, are suitable for binding salts with the free acids (R ¹ = H). Examples include: alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine,

Triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, glucosamine, lysine, ornithine and arginine. The clathrates with α-, β- or γ-cyclodextrin are obtained analogously to the specification WO 87/05 294. β-cyclodextrin clathrates are preferred.

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 pharmacological properties for prostacyclin derivatives of the formula I:

Reduction in peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and triggering of platelet thrombi, myocardial cytoprotection and thus reduction in systemic blood pressure without simultaneously reducing stroke volume and coronary blood flow; Treatment of stroke, prophylaxis and therapy of coronary thrombosis, myocardial infarction, 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, reduction of pulmonary vascular resistance and the use of pulmonary blood Instead of heparin or adjuvant during dialysis or hemofiltration, preservation of blood plasma preserves, especially of blood platelet preservation, inhibition of labor pains, treatment of pregnancy toxicosis, increase in cerebral blood flow etc. Furthermore, the new prostaglandin analogues have antiproliferative properties.

EP 86 404 B1 describes the use of carbacyclins for the prophylaxis and therapy of ischemic attacks of the CNS system, for cytoprotection in the liver and in the pancreas, and the combination with β-blockers or diuretics. DE 34 27 797 C2 discloses the cytoprotection of the kidney and the suitability of the prostacyclin derivatives of the formula I for the treatment of organs to be transplanted. DE 35 26 362 A1 describes 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 discloses the combination of the prostacyclin derivatives of the formula I with fibrinolytics to prevent rethrombosis after thrombosis. DE 3608 088 describes the clathrates of the carbacyclin derivatives of the formula I. From DE 36 31 169 A1, in addition to the administration forms described in EP 11 591 B1, the topical administration form is known.

DE 41 35 193 C1 describes the use of the abovementioned compounds as an additive for preventing or treating disorders of the microcirculation - that is to say the terminal current path which cannot be imaged (sub-macroscopic vessels) - after administration of X-ray, ultrasound or MRI contrast media.

The use of the prostaglandin derivatives claimed in the context of this invention is not mentioned or suggested in any of the above published documents or patents or in the other literature.

Surprisingly, studies on animal models have shown that the compounds mentioned can be used successfully in improving imaging by means of X-ray, ultrasound, nuclear or MRI contrast media. The concentration range of the prostacyclin derivatives added to the contrast agents is preferably 0.1-100 ng / ml. In this concentration range, imaging improves even without the addition of contrast agents, especially in MRI diagnostics and angiography.

The use of urea to improve imaging has not been described in any publication. The only study reported in the literature relates to the change in diuresis after administration of sodium iodide by the addition of urea (A. Roseno, Klin. Wochenschr. 25: 1165-70 [1929]). This work primarily aimed at faster excretion and thus faster detoxification of sodium iodide, which is highly toxic compared to today's X-ray contrast media. It has now been found that the addition of urea to today's X-ray contrast media is surprisingly able to significantly improve the imaging in the urogram, although urea leads to a strong osmodeuresis and thus dilution of the contrast medium excreted. The less concentrated contrast agent in the urine should actually cause a poorer image quality. Correspondingly unfavorable results are obtained after adding mannitol to a nonionic contrast medium (I. Lovelt et al., In Recent Developments in Nonionic Contrast Media, V. Taenzer, S. Wende: Schwier. Röntgenstr. Suppl. 128: 105-7 [1989 ]). The concentration range of the urea added to the contrast media is preferably 10-150 mg / ml. In this concentration range, imaging also improves without the addition of contrast agents, especially in MRI diagnostics and angiography.

Examples

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

1. Addition of lloprost to Ultravist: imaging of vessels

A rabbit with a body weight of approx. 3 kg was injected with the nonionic, low-osmolar X-ray contrast agent Ultravist ^® -300 (active ingredient: lopromide (INN)) 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 lloprost to the contrast medium. The result is shown in Fig. 2.

After a further resting phase, the examination was carried out again. This time, however, the injection consisted of Ultravist ^β -300 without the addition of iloprost.

Result:

The addition of 10 ng / ml lloprost to Ultravist ^® -300 greatly improved the angiogram. A new injection of Ultravist ^® -300 again showed the original - less pronounced - angiogram.

2. Addition of lloprost 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 ^β -370 (active ingredient: lopromide (INN)). The dose was 2 ml / kg, the injection rate was 1-1.5 ml / sec. Immediately afterwards, an initial program was recorded (FIG. 3).

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

After a further resting phase, the examination was carried out again. This time, however, the injection consisted of Ultravist ^® -370 without the addition of iloprost.

Result:

The addition of 10 ng / ml lloprost to Ultravist -370 significantly improved the urogram.

3. Addition of urea to isovist: use in urography

The investigation was designed as a block test. In the first block, 3 animals were treated with Isovis »t • -280 (active ingredient: lotrolan (INN)) and 3 animals with isovist ^β -280 + 52 mg urea / ml. In the second block - 3 days later, the animals were given the other formulation.

Result:

The addition of 52 mg of urea to one ml of lsovist ^® -280 significantly improved the urogram (Fig. 5 and 6), especially the kidney cups are more contrasted.

Claims

claims

1. Use of a prostaglandin derivative to improve imaging in X-ray, ultrasound, nuclear or MRI diagnostics.

2. Use of a prostaglandin derivative in combination with a contrast agent to improve imaging in X-ray, ultrasound, nuclear or MRI diagnostics.

3. Use of prostacyclin derivatives of the general formula I

wherein

R ¹ is _β hydrogen or a Cι-C alkyl radical, n stands for the numbers 0 to 3,

X, Y independently of one another represent a —CH ₂ group or an oxygen atom, Z represents hydrogen, fluorine or CN,

A for a transient -CH = CH- or a -C = C group,

W stands for a free or functionally modified hydroxymethyl group on the hydroxyl group, where the hydroxyl group can be α or β, D stands for a straight-chain or branched d-Cs-alkylene group,

E represents a -C «C group, R ^{2 represents} a C -C ₂ alkyl group,

R ^{3 stands} for a free or functionally modified hydroxy group, as well as their cyclodextrin clathrates, and - if R ^{1 is} hydrogen - their salts with physiologically compatible bases, to improve imaging when using X-ray, ultrasound, nuclear or NMR Contrast agents according to claim 1 or 2.

4. Use of lloprost, cicaprost, eptaloprost or a cyclodextrin clathrate of these compounds according to claim 1 or 2.

5. Use of 5 - [(E) - (1 S, 5S, 6S, 7R) -7-hydroxy-6 - [(3S, 4S)] - 3-hydroxy-4-methyl-1, 6-nona- diinyl] -bicyclo [3.3.0] -oct-3-ylidene] -pentanoic acid, δ-KEHlS.SS.eS R -hydroxy-e-fSS ^ S ^ -hydroxy - ^ - methyl-l .e-nonadiinyl ] -bicyclo [3.3.0] -oct-3-ylidene] -5-fluoro-3-oxapentanoic acid or a cyclodextrin clathrate of these compounds according to claim 1 or 2.

6.Use of Ataprost (INN), Beraprost (INN), Ciprosten (INN), CS 570 (INN), FCE 22509 (INN), Naxaprosten (INN), RS 93427 (INN), SC 39902 (INN), Taprosten ( INN) or a cyclodextrin clathrate of these compounds according to claim 1 or 2.

7. Use of urea to improve imaging in X-ray, ultrasound, nuclear or MRI diagnostics.

8. Use of urea in combination with a contrast medium to improve imaging in X-ray, ultrasound, nuclear or MRI diagnostics.

9. Use of a prostacyclin derivative according to claim 1, 2 or 3 together with urea to improve imaging in X-ray, ultrasound, nuclear or MRI diagnostics.

10. Use of a prostacyclin derivative according to claim 1, 2 or 3 together with urea to improve imaging in X-ray, ultrasound, nuclear or MRI diagnostics in combination with a contrast agent.