DE1809014A1 - X-ray contrast media - Google Patents

Description

Pharmacia Aktiebolag Uppsala / Sweden

X-ray contrast medium Addendum to patent application P 16 17 743 · 8 - our number # 14 3Jt>

The patent application P 16 17 743.8 relates to an X-ray contrast medium, which is characterized in that it is made from a water-soluble linear or branched polymer having an average molecular weight of at least 5,000, preferably at least 10,000 or contains the same as a shading substance, the polymer consisting of alternating groups of one or more Iodobenzene derivatives and straight or branched, hydroxyl-containing, aliphatic intermediate bridges with 3 to C atoms, preferably 3 to 10 C atoms, optionally are interrupted by one or more oxygen bridges.

As set out in the above patent application, have the X-ray contrast media claimed therein compared to the previously customary, known shadowy ones

909833/1432

18090U

_ 2 -

Substances with a low molecular weight (monomers or in some cases dimers) have the advantage that they have different absorption and excretion properties and thereby deliver new possibilities for diagnostics.

Due to their hydroxyl group content, they are in the middle easily soluble and physiologically well tolerated. Your high Molecular weight also leads to lower osmotic pressures than is the case with conventional agents.

To the various body cavities that are made visible by the contrast agent of the above patent application belongs to the gastrointestinal tract. In this case, the high molecular contrast agent is perorally in solid form or administered in the form of a solution. It then passes through the gastrointestinal tract without being absorbed. The body will In this way influenced by the supplied agent in the least possible way. It is also possible to use the Verlau to make the intestine visible by adding the high-molecular contrast agent rectally, e.g. in the form of an enema .

Other body cavities that can be visualized are for example the blood vessels and the heart j the contrast agent disappears because of its high molecular weight after its injection from the blood much more slowly than the usual known contrast media. There the molecular size of the contrast agent below the Kidney threshold, the drug can be excreted in the urine and valuable information can be obtained obtained through the urinary tract. More examples of

909833/1432

18090U

the use of iodine polymers are the fields of Hysterosalpingography, cholangiography, lymphography, Urethrography and sialography.

After the administration of the contrast medium, the body parts to be examined can be X-rayed or the X-ray image can be observed directly on the screen. Furthermore, everyone can usual X-ray techniques are used.

The dose of contrast agent that is administered is selected to be sufficient for the particular examination Contrast is achieved.

Carriers for the polymers can be conventional additives e.g. water for injection solutions and other common additives for tablets.

ffie continued in the above patent application can be used as iodobenzene derivatives, for example, triiodobenzene derivatives, preferably 2,4,6-triiodobenzoic acid derivatives, use. The latter can be, for example, 3f5-diamino-2,4,6-triiodobenzoic acid or 3-Amino-5-aminomethyl-2,4,6-triiodobenzoic acid derivatives or to 5-amino-2,4,6-triiodisophthalic acid monoamide derivatives such as Act 3i5-diacyl-amino-2,4,6 ~ triiodobenzoic acid derivatives, in which the acyl group is a lower acyl group having not more than 5 carbon atoms, preferably one Is acetyl or propionyl group.

909833/1432

18090H

The polymer can, for example, consist of alternating groups of the formula

-N-C C-N-

Il

COOH

in which R is a lower acyl group with not more than 5 carbon atoms or a carbon atom or their physiologically harmless salts and bridges of the formula -A- be built up. A is an alkylene group having 3 to 30, preferably 3 to 10 carbon atoms, ie substituted by one or more hydroxyl groups and optionally by one or more oxygen bridges is interrupted. The bridging group A can have the following formula, for example:

-CH ₂ .CH (OH) .CH ₂ .0.CH ₂ .CH (OH) .CH ₂ - or -CH ₂ .CH (OH) .CH ₂ .0.CH ₂ .CH ₂ .0.CH ₂ .CH (OH) .CH ₂ - or -CH ₂ -CH (OH) .CH ₂ .0. (CH ₂ J ₄ .0.CH ₂ CH (OH) .CH ₂ - or -CH ₂ -CH (OH ) .CH ₂ .0.0H ₂ .CH (OH) .CH ₂ .0.CH ₂ .CH (OH) .CH ₂ - or -CH ₂ .CH (OH) .CH ₂ -.

Further examples of iodobenzene derivatives in the polymer are:

or

COOH COOH

909833/1432

1'809OH

or their physiologically harmless salts.

A contrast medium preparation can be in the form of an aqueous solution or a mixture with a physiologically harmless one solid support. It can be in tablet form or other suitable dosage form are present and must contain one or more of the aforementioned polymers as shading substances.

If the polymer used as a contrast medium contains acid groups, i.e. one or more carboxylic acid groups, which is the case, for example, with agents based on iodobenzoic acid derivatives is the case, the product is generally used in the form of a physiologically harmless one Salt, e.g. as sodium, tris-hydroxymethylaminomethane or methyl glucamine salt.

The hydroxyl group content of the polymer can vary. In general, the hydroxyl group content becomes like this chosen that it is on average not less than one: corresponds to hydroxyl group per bridge. It is also possible, to choose the hydroxyl group content so that there are two hydroxyl groups per bridge. Should the means in terms of to obtain a greater solubility in water for its intended use, the bridge must on average have about 4 or more hydroxyl groups. If the number of hydroxyl groups on the bridge is insufficient, it is possible to increase their number, for example by introducing glycerol ether groups.

The iodine content of the polymer can vary depending on the purpose of use in a wide range achwankeni In general, the iodine content should exceed 15 about i>. Usually over-

909833/1432

if the iodine content exceeds 20 ^e / o considerably and is, for example, between 25 and 55 '/ »·

It has now been found that polymers with the structure described above can also be used as X-ray contrast media, but whose average molecular weight (weight average) is at least 1700, preferably at least 1900 and less than 5000, and in which at least 3 iodobenzene groups, preferably at least 4 iodobenzene groups, ie 4, 5 or 6 are included . The preferred number of carbon atoms in the bridge members is 3-20.

With regard to their absorption and excretion properties, their osmotic pressure and their viscosity, the contrast media according to the invention occupy an intermediate position between the contrast media of patent application P 16 17 743 · 8 and the low molecular weight known contrast media. As a result, they offer further options for changing the diagnostic techniques, which is particularly valuable in certain cases . Because of their excellent solubility, brought about by the content of hydroxyl groups, and the high degree of physiological compatibility, the contrast media according to the invention can be used for X-ray urography and blood vessel examinations. In addition to the urinary tract and blood vessels, the gastrointestinal tract can also be made visible

The polymer according to the invention can be produced by copolymerization of substances containing the iodobenzene derivative as well contain other functional groups, with a bifunctional substance that forms an aliphatic bridge with 3 to 30 carbon atoms and hydroxyl groups or groups such as Epoxy groups that lead to the formation of hydroxyl groups in the

909833/1432

The course of the polymerization are capable of containing, are produced.

A particularly favorable method for the preparation of the invention Compounds consists in the implementation of a bifunctional triiodobenzoic acid derivative such as 3,5-biacylamino-2,4,6-triiodobenzoic acid with a piepoxide such as bis- / 5,3-epoxypyropyl7ether or 1,2-ethanediol diglycidether or 1,4-butanediol diglycid ether or glycerol diglycid ether or the corresponding halohydrins, preferably the chlorohydrins or bromohydrins or with epichlorohydrin or epibromohydrin, preferably in an alkaline medium. Another example is the polymer , which one by appropriate polymerization of 3-amino-5-aminomethyl-2,4 »6-triiodobenzoic acid or a Derivative thereof such as an acyl derivative, namely the acetyl derivative.

A further example is a polymer that can be cited by appropriate polymerization of the above-mentioned diepoxides with 5-amino-2,4,6-tri3odisophthalic acid monoamide derivatives, for example with 5-acylamino-2 _f 4y6-triiodo-N-alkylisophthalic acid monoamides, such as S-acetylamino ^^ ö-trijod-N-methylisophthalic acid monoamide, receives.

The bridges formed from the diepoxides contain hydroxyl groups. If epichlorohydrin is used, preserves one hydroxyl group, and when using the diepoxides, at least two hydroxyl groups are obtained in the bridge.

909833/1432

18090U

Examples of the bridging groups are, except don already above for the patent application P 16 1? 743 8 described, the groups of the following formulas;

-Cup. CH (OH) .CH ₂ .0. CK ₂ -. CH (OK). CH ₂ . U. (CH ₉ ) _P. 0. CH ₂ . CH (OH). . CHoTc. CH ₂ . CH (OH). CH ₂ -. . - -_ '

or -

-CIi ₂ .CH (OH) .CH ₅ X-CH ₂₄ -CH (OH) .CHp.O. (CH ₂ ) ^. O.CK ₂ .CH (OH). CH ₂ .O.CK ₂ .CH (OH) .CH ₂ - "
cdor
* -CH ₂ . CIi (OH J. CH (OH). CHp-.

The desired average molecular weight of the polymers k'-nn can either be obtained by the raw materials are used in proportions that match the desired Corresponding to the product and allowing it to react to the end or, if other proportions of the starting materials are selected the reaction is interrupted at the point which the desired degree of polymerization has been achieved.

Similar to other polymers, the products can be by fractional precipitation or by gel filtration fruktionicror ..

Other polyfunctional oils can also be used during the polymerization Substances like NH, or amines like boispijlswoiso Diamino, or polyhydroxy compounds such as pentaerythritol, to facilitate the same can be added.

If the content of Ilydroxylgruppen are increased and so that the solubility is also to be increased, for example for agents to be used orally, those containing hydroxyl groups can be used Polymers with glycide in the presence of a

909833/1432

alkaline-reacting agent with the formation of glycerine ether, implemented.

In the following Examples 1-6 a copolymer was used from 3 /:> - Diacetylamino-2,4,6-triiodobenzoic acid with 1,4-butanediol diglycidether used, which had been prepared by the fact that the starting materials for 24 hours. In Caustic soda Each uras > -t ζσι left. The product can thereby cleaned by precipitating it with hydrochloric acid, dissolving it again as sodium salt and then again with hydrochloric acid fails. From the polyacid obtained can be passed through Neutralization, e.g. with NaOH or methylglucamine solutions produce. If necessary, the neutral salt solution, for example by fractional precipitation with acetone, be fractionated.

If the agent according to the invention is in the form of an aqueous solution, it is expedient to contain / the polymers in concentrations of at least about 10-20 $, depending on the area of application. Concentrations above 30 or 40 ° and even above $ 50 can also be considered.

The following examples serve for further explanation the invention:

Example 1:

A solution was prepared by adding 50 g of a polymer having an average molecular weight of about 4000 in the form of its methylglucamine saltec and 0.8 g of NaCl was dissolved in enough water to create a tight received from 100 ecm. The pH was adjusted with HCl and ITaOH

909833/1432

BATH ORIGINAL

18090U

set to 7 »" * "to 7.4. The solution was filtered and filled into bottles which were capped and sterilized in an autoclave.

This solution was injected into the blood vessels of rabbits, after which these blood vessels and the cavities of the heart are made visible by X-rays and x-rays were taken. When x-raying the iliac area and then making it X-rays showed that the renal pelvis, the ureter and the bladder with the contrast medium were filled.

Example 2; ,

A solution was made by adding 30 grams of a Polymer having an average molecular weight of about 3400 in terms of its methylglucamine salt and Dissolve 0.8 g of NaCl in enough water to make a solution Received in a lot of IOC ecm. The pH was Adjusted to 7.3 to 7.4 with HCl and NaQH. The solution was filtered and filled into bottles which were closed and sterilized in an autoclave.

- intravenous

The solution was injected into rabbits /. When x-raying the Kieren area and when making x-rays it was found that the renal pelvis, ureter and bladder were filled with the contrast medium.

909833/1432

18090H

Example 3s

A solution was characterized hurgestellt, CKSS mn η <VO A his Methylglucaminsalzos dissolved a polymer having an average molecular weight of about 3000 in the form in so much water that a solution was obtained in an amount of ECM 100th The pH / size was adjusted to 7.3 to 7.4 with HCl and NaOII. The solution was filtered and filled into bottles, which were then sealed and sterilized in an autoclave.

The solution was injected intravenously into rabbits. At the X-ray of the Nieron area and the HorstclJou von X-rays showed that the renal pelvis, the ureter and bladder were filled with the contrast medium.

Example 4;

A clysteroid was made by adding 40 grams of one Polymer having an average molecular weight of about 4000 in the form of its sodium salt and 0.5 g NaCl in so much Vasser dissolved that you could get one. Solution in one Received amount of 100 ecm with a pH iVert = 7.

The celiac animal was administered to rabbits through the rectum, after which the intestines could be visualized by x-rays and x-rays of the same could be made.

BATH 909833 / U32

1808014

Example5 | "·

A solution was prepared by * that 40 g of a ■ polymer having an average molecular weight ■ From about 4OÖÖ in the form of its sodium salt and O * 2 q NaCl dissolved in so viol water such that a solution was obtained in an amount of 100 cc * The pH was adjusted to 7 *

"The solution was administered orally to rabbits, which fell · the Magon's intestinal tract visualized by X-rays' and x-rays could be made.

Example Gg

There were 61.4 g of 3-acetylamino 5-acetylamino-2,4,6-tri- _{t-iodobenzoic} acid was dissolved in 60 cc of 4N Natronlaugc * After six hours have been under stirring for 17 ecm 1 ^ butanediol "diglycidäthor dropwise very slowly added Khan let the reaction mixture for one day at 20 ⁰ C are. the polyacid thereby that formed was precipitated with 3N hydrochloric acid. the addition of 4N sodium hydroxide the product as K atrium al z. was dissolved. Thereafter, the polyacid was again by the addition of 3N hydrochloric acid "precipitated * The product was washed with water and vacuum-dried ^{at 50 0 G.} The product is soluble in the form of its sodium salt * Its average molecular weight was about 3800.

25 g of this polymer in the form of its acid was thereby dissolved by adding water and methylglucamine, with the amount of water was chosen so that a solution amount of 50 ecm and ^ lethylglucamine was chosen so,

9 0 9 8 3 3 / H 3 2

18090H

that a pH of 7.3 was obtained. The solution was filtered and filled into bottles, which are closed and interleaved in an autoclave.

The solution was injected into the Venv.n from rabbits could be visualized after which the veins by X-rays. In addition, the solution was injected into the arteries of rabbits, whereupon not only the artorion but also the associated veins could be made visible by X-rays. When the corresponding Mongo was injected with a conventional monomeric contrast medium into the same arteries, the associated veins could not be made visible in the same advantageous way. The X-ray contrast medium according to the invention therefore opens up new diagnostic possibilities.

Example 7:

There were 6 ^1, 4 g of 5-acetylamino-2,4,6-triiodo-N-methylisophthaisäuremonoamid dissolved in 60 cc of 4N sodium hydroxide solution. Then 18 ecm of 1,4-butanediol diglycidether were added very slowly dropwise with stirring for 6 hours. The reaction mixture was left for 24 hours. stand at 2ü ° C for a long time. The product that formed was precipitated with 3N hydrochloric acid. The polyacid was redissolved by adding 4N sodium hydroxide solution. The product was then reprecipitated in the form of its acid by adding so much 3N hydrochloric acid that no more precipitate was formed. The product was washed with water and vacuum dried at 50.degree. The product is soluble in the form of its sodium salt. Its average molecular weight was about 4200 «

909833 / U32

BATH

18090H

25 g of duD polymer in the form of its acid were thereby dissolved in water by adding a large amount of methyl glucaride, as was necessary to. adjust the pH * Vert to 7.3, where If violet water has been used, let - ^ O com tor solution received. The solution was filtered and bottled, which one vorschloß un.l sterilized in an autoclave.

The lorning was injected into the veins of rabbits, ψ whereupon the blood vessels could be made very clearly visible. The solution was also injected into the torsion of rabbits, whereupon it was not only possible to make this interference visible, but also the associated veins were visible on the corresponding x-ray. As a manual, a corresponding menu of a customary monomer. When contrast medium was injected into the same artery, the associated veins could not be made visible in the same place before the ceilings. Thanks to the invention of x-ray contrast media, lahor nouo isch · '. ⁵ possibilities.

Bc-ispioi 6;

-1> 4 (S J-ACotylamino-5-fl.cetylamino-2, 4,6-tri; iodobenzoic acid are dissolved in 7C ecm 4N sodium hydroxide solution. Thereafter, -12.8 ecm glycidyl were stirred for 6 hours very slowly added dropwise at 20 ° C. The reaction device was left to stand for 2 days. (During the reaction, the water atoms attached to the nitrogen atom were exchanged for the substituent -CHp-CH (OH) .CH ₂ .OH .) Then 18 ecm of 1,4-butanediol diglycidether were very slowly dropwise with stirring for 6 hours at 20 ° C

909833/1432

18090U

~ 15 -

The reaction was allowed mixture for 24 hours lnng bni stand 20 ⁰ C, (The diepoxide polymerizing the Jodmonomereneinheiten by reaction with the hydroxyl groups in ve ion aforementioned Glycefinreötön ") The ReviktioiiB was ^ emic with 6N hydrochloric acid to a pH-V / ert neutralized by 7 and the sodium salt of the polymer precipitated with acetone ;. Bas product was ftelöct in some water and then re-precipitated with acetone and vacuum dried at tJcr.jtc- 5O ^C C * The slight change -in 1 _f 4- Butandioldiglycidäther were products ^get! ": ltuii, let a -mdores average molecular interioriiMlb rlus possessed the framework according to the invention"

Products were characterized by an excellent Ι / λγ-3 ic-Möit in way nor, as a result of the chosen polyhyii IOX ₁ V bridge υ between the iodine monomer units * The products were also easily soluble in gastric acid and were therefore particularly suitable for oral use, when the Ma /; en-Darrntr £ kt is to be made visible Üios * \ vurdo detected by reacting neutral solutions of the product (z * B 50 g of Substans / 100 cc lot.nmr.) orally at Rf. were administered, whereupon the gastric diii'fiinct could be made clearly visible *

Example 9;

A number of experiments have been carried out carried out in Example 8 were completely analogous with the Deviation that instead of the compounds used in Example 8, the same amounts of 5-acetylamino-2,4,6-triiodo-H-methylisophthalic acid monoamide, Glycid and 1,4-butanediol diglycid ether were used. Also in this

0 98 3 3/1432 _BAD original

18090U

In this case it was possible, by changing the amounts of bridging diepxidic products, to reduce the number of non-torochodic average molecular weights within ics scope of the invention were to be obtained after the reaction with glycide.

The sodium salt of the products was in both water and also easily soluble in gastric acid and proved to be particularly suitable for visualizing the gastrointestinal tract, which could be proven when one in rats and rabbits solutions of the product in orally administered at a concentration of 40 or 50 g of the substance per 100 ecm of solution.

In the same way as described in the above example, X-ray images can be obtained with polymers of different average molecular weight, which are obtained, for example, by polymerizing 3,5-diaoetylamino-2,4,6-triiodobenzoic acid with 1,2-ethanediol diglyidic acid or from 3-Ämino-5-aminomethyl-2,4,6-triiodobenzoic acid or its derivatives with diepoxides such as 1,4-butanedicldiglycidether or 1,2-ethanediol diglycidether were obtained. Other useful examples are polymers obtained by polymerizing bifunctional 5-amino-2,4,6-triiodisophthalic acid monoamide derivatives, such as, for example, 5-acylamino-2,4,6-triiodo-N-alkylisophthalic acid monoamide, in which the acyl and alkyl radicals are lower ^ReS erha ¥ l ⁽ en ^m ^ ^ / u ^^ bi ¹ ^ ¹²¹¹¹ ^ - ⁰ S above type /. Examples of such polymerization products are those obtained by polymerization of 5-acetylamino-2,4,6-triiodine-N- methylisophthalic acid monoamide with 1,4 ″ -Butandioldiglycidäther, 1,2-Äthandioldiglycidäth'er, epichlorohydrin or 1, S-Grlycerindiglycidäther can be obtained in alkaline aqueous solution.

909833 / U32

Claims (3)

Claims; 1 »X-ray contrast medium, which consists of a water-soluble linear or branched polymer or contains the same as a shading substance, the polymer consisting of alternating groups of 2,4,6-triiodobenzoic acid-S ^ -derivates and straight or branched, hydroxyl group-rich aliphatic Zv / Ischenbrücken with 3 to 30 G-atoms, which are optionally interrupted by one or more oxygen bridges, built up, according to patent application P 16 17 743 »8, characterized in that the polymers have an average molecular weight of at least 170Ω, preferably at least 1900, and not more than 5000 and at least 3, preferably at least 4 | 2 _? 4 »6-! Drijodber ^ zoesäure-3,5-Derivafce contain. 2. Means according to claim I, characterized in that the briickenbildericle group has the formula: .GHC Oil), OHg. O.CHp.CH (OH) _f CH ₂ .0, (CH ₂ ) ₂ , 0.CH ₂ .CH (OH). ₂ , D, GH ₂ .GHfOH), CH ₂ ^
or , GHf OH) »GH ₂ , 0, GH _{2 f} OH (OH) .CH ₂ .0. (CH ₂ ) ₄ »P.GH. ₂ CH (OH). ₂ »0, PBg-. OH (OH), 0IJ ₂ ^
or , GJi (OH), OH (OH), CH ₂ -, _p 3. Agent according to one of the preceding claims, characterized in that it consists of oiner aqueous. Löaurig or i'in CromiBch with a physiologically harmless solid
Carrier, which is preferably in the form of tablets, consists of one or more polymers. Pure Pharmacia Aktiebolag
Uppsala / Sweden BATH