DE1809014B2 - X-RAY CONTRAST AGENT - Google Patents

Description

(4-

C-J

/ \
C CX-

J-C C-J

COOH

I!

X = N- -CH ₁ -N-

• CO-N-

M> 50 (X)

or their physiologically acceptable salts as a shade-giving substance, with

X = N-

-CH ₁ -N-

or

■ CO-N-

and A is an alkylene group having 3 to 30 carbon atoms, those having one or more hydroxyl groups is substituted and optionally interrupted by one or more oxygen bridges can, means, and wherein the polymer is composed of alternating groups of 2,4,6-triiodobenzoic acid-3,5-derivatives and the groups A is built up, according to Patent 16 17 743. characterized in that the polymers a Have an average molecular weight of at least 1700 and not more than 5000 and at least contain three 2,4,6-triiodobenzoic acid-3,5-derivatives.

2. X-ray contrast medium according to claim 1, characterized in that the polymers are a Have an average molecular weight of at least 1900 and not more than 5000.

3. X-ray contrast medium according to one of claims 1 and 2, characterized in that the Polymers contain at least four 2,4,6-triiodobenzoic acid-3,5-derivatives.

~ '"

The patent 16 17 743 relates to an X-ray contrast medium based on 2,4,6-triiodobenzoic acid-3,5-derivatives, which is characterized in that it a water-soluble linear or branched polymer of the general formula

C-J

1 y \ \

NC CX-) (-A-)
JC CJ

COOH

60

M> 5000

or their physiologically tolerable salts as schat and A is an alkylene group with 3 to 30 carbon atoms, which is substituted with one or more hydroxyl groups and optionally by one or more oxygen bridges can be interrupted, means, and wherein the polymer consists of alternating Groups of 2,4,6-triiodobenzoic acid-3,5-derivatives and the groups A is built up.

As set forth in the above patent, the claimed therein have x-ray contrast agents compared to the previously customary, known shadowing substances with a low molecular weight (Monomers or in some cases dimers) have the advantage that they have different absorption and excretion properties and thus provide ncüc possibilities for diagnostics.

Due to their hydroxyl group content, the agents are readily soluble and physiologically well tolerated. Their high molecular weight also leads to lower osmotic pressures than at usual means is the case.

To the various body cavities visible through the contrast medium of the above patent One of the parts of the gastrointestinal tract. In this case it becomes high molecular weight Contrast media administered orally in solid form or in the form of a solution. It then happens that Gastrointestinal tract without being absorbed. The body is fed in this way by the Affected funds in the least possible way. It is also possible to see the course of the intestine to make by rectally applying the high molecular weight contrast agent, e.g. B. in the form of an enema, supplies.

Other body cavities that can be made visible are, for example, the blood vessels and the Heart; the contrast agent disappears after its injection because of its higher molecular weight out of the blood much more slowly than the usual known contrast media. Since the molecular size of the If the contrast agent is below the kidney threshold, the agent can be excreted in the urine and valuable information about the urinary tract can be obtained. More examples of usage of iodine polymers are the areas of hysterosalpingography, cholangiography, lymphography, Urethrography and sialography.

After the administration of the contrast medium, the body parts to be examined can be examined Take X-rays or the X-ray image can be viewed directly on the screen will. All customary X-ray techniques can also be used.

The dose of contrast agent that is administered is selected to suit the particular examination a sufficient contrast is achieved.

Carriers for the polymers can be customary additives, e.g. B. Water for injection solutions and other common additives in tablets.

As further stated in the above patent. it is the 2,4,6-triiodobenzoic acid derivatives for example by 3,5-diamino-2A6-triiodobenzoic acid or S-amino-S-aminomethyl-IAo'-triiodobenzoic acid derivatives or about 5-amino-2,4,6-triiodisophthalic acid monoamide derivatives like 3,5-diacyl-

amino-2A6-iriiodobenzoic acid derivatives, in which the Acyl group is a lower acyl group with no more than 5 carbon atoms, preferably an acyl group or propionyl group.

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

I c

- N — C C - N-

J-C C-J

COOH

in which R is a lower acyl group with not more than one or more hydroxyl groups substituted 5 carbon atoms or a hydrogen atom and optionally by one or more acidic terms or whose physiologically harmless salt bridges are interrupted. The bridging zcn and bridges of the formula - Λ - built up group A can be, for example, the following formula. A is an alkylene group with 3 to 30, 25 seats:
preferably 3 to 10 carbon atoms, mil

or

or

or

-CH, CH (OH) CH ₂ O CH ₂ CH (OH) CH ₂ -
-CH ₂ · CH (OH) -CH ₂ -O CH ₂ -CH ₂ -O- CH ₂ · CH (OH) · CH ₂ -CH ₂ -CH (OH) -CH ₂ -O- (CH ₂ I ₄ O CH ₂ CH (OH) CH ₂ -CH ₂ -CH (OH) -CH ₂ O ■ CH ₂ CH (OH) -CH ₂ -O- CH ₂ CH (OH) CH ₂ -

or

-CH ₂ -CH (OH) -

Further examples of iodobenzene derivatives in the polymer are:

CO —N—

COOH

or their physiologically harmless salts.

A contrast agent preparation can be in the form of an aqueous solution or a mixture with one physiologically harmless solid carriers are present. It can be in the form of tablets or another Suitable dosage form must be one or more of the aforementioned polymers contained as switching substances.

Since the polymer used as a contrast agent contains carboxyl groups, the product is used generally in the form of a physiologically acceptable salt, e.g. B. as sodium, tris-hydroxymethylaminomethane or methyl glucamine salt. The hydroxyl group content of the polymer can vary. In general, the hydroxyl group content becomes chosen so that on average it is not less than one hydroxyl group per bridge is equivalent to. It is also possible to choose the hydroxyl group content so that two hydroxyl groups per Bridge are in place. Should the agent have a stronger solubility wedge with regard to its intended use preserved in water, the bridge must have an average of about four or more hydroxyl groups. If the number of hydroxyl groups on the bridge is insufficient, it is possible to increase their number increase, for example, by introducing glycerol ether groups.

The iodine content of the polymer can vary within wide limits depending on the intended use. In general, the iodine content should exceed about 15%. Usually the iodine content exceeds

fl

even 20% considerably and is between 25 and 55%, for example.

It has now been found that X-ray contrast media can also use polymers with the structure described above, which have an average molecular weight of at least 1,700, preferably at least 1,900 and not more than 50,000 have and at least three, preferably at least four ^ Aö-triiodobenzoic acid-S ^ -dcrivate, d. H. 4, 5 or 6, included.

The preferred number of carbon atoms in the bridge members is 3 to 20.

The contrast media according to the invention take with regard to their absorption and excretion properties, their osmotic pressure and their viscosity an intermediate position between the contrast media of patent 16 17 743 and the low molecular weight known contrast media. they offer consequently further possibilities to change the diagnostic techniques, which in certain cases especially is valuable. Due to their excellent solubility due to the hydroxyl group content and the high degree of physiological tolerance, the contrast media according to the invention for X-ray urography and blood vessel examinations use. 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 which form the triiodobenzoic acid derivative as well as other functional groups containing a bifunctional substance, the one aliphatic bridge with 3 to 30 carbon atoms and hydroxyl groups or groups such as epoxy groups, which are capable of forming hydroxyl groups in the course of the polymerization, contains, getting produced.

A particularly favorable method for the preparation of the compounds according to the invention consists in Reaction of 3,5-Diacyla.nino-2,4,6-triiodobenzoic acid with a diepoxide such as bis- [2,3-F.poxypropyl] -ether or 1,2-Älhandioldiglycidäther or 1,4-Bulandioldiglycidäther or glycerol diglycidether or the corresponding halohydrins, preferably the Chlorohydrins or bromohydrins or with epichlorohydrin or epibromohydrin, preferably in an alkaline one Medium. Another example is the polymer that can be obtained by appropriate polymerization of 3-amino-5-aminomethyl-2,4,6-triiodobenzoic acid or a derivative thereof, e.g. B. an acyl derivative, viz the acetyl derivative. receives.

As a further example, a polymer may be mentioned which is obtained by appropriate polymerization of the above-mentioned Diepoxides with 5-amino-2,4,6-triiodisophthalic acid monoamide derivatives, z. B. with 5-acyl-amino-2,4,6-triiodine-N-alkylisophthalic acid monoamides, like S-acetylamino ^ Ao-triiodo-N-methylisophthalic acid monoamide. receives.

The bridges formed from the diepoxides contain hydroxyl groups. When using epichlorohydrin one gets a hydroxyl group, and when one uses the diepoxides one gets at least one two hydroxyl groups in the bridge.

Examples are the bridging groups other than those already described in patent 1617743 the groups of the following formulas:

-CH, • CH (OH) • CH ₂ OCH, - CH (OH) • CH, ■ O • (CH ₂ ), • O • CH ₂ • CH (OH) CH ₂ • OCH, • CH (OH) CH ₂ -

-CH ₂ ■ CH (OH) CH ₂ OCH ₂ - CH (OH) CH ₂ -O- (CH ₂ I ₄ - O CH ₂ CH (OH) CH ₂ O CH ₂ CH (OH) CH ₂ -

-CH ₂ ■ CH (OH) CH (OH) CH ₂ -

The desired average molecular weight of the polymers can either be obtained thereby that you use the starting materials in proportions that correspond to the desired product and lets react to the end or, if other proportions of the starting materials are chosen, the Interrupting the reaction at the point at which the desired degree of polymerization has been reached.

Similar to other polymers, the products can be fractionated or precipitated Fractionate gel filtration.

During the polymerization, other polyfunctional substances such as NH ₃ or amines such as diamines or polyhydroxy compounds such as pentaerythritol can also be added to facilitate the same.

If the content of hydroxyl groups is increased and thus the solubility is also increased should, for example for oral agents, the hydroxyl-containing polymers with Glycid in the presence of an alkaline reacting agent with the formation of glycerol ether. implemented will.

In the following Examples 1 to 6, a copolymer was used from 3,5-diacetylamino-2,4,6-triiodobenzoic acid with 1,4-bulandiol diglycidether used, the had been produced by converting the starting materials into sodium hydroxide solution for 24 hours let. The product can be purified by precipitating it with hydrochloric acid as the sodium salt dissolves again and then precipitates again with hydrochloric acid. Let out of the polyacid obtained by neutralization, e.g. B. using NaOH or methylglucamine solutions. Possibly the neutral salt solution can be fractionated, for example by fractional precipitation with acetone.

If the agent according to the invention is in the form of an aqueous solution, it is advantageous that the Polymers in concentrations of at least about 10 to 20%, depending on the application, contained therein are. Concentrations above 30 or 40% and even above 50% can also be considered come.

The following examples serve to further illustrate the invention:

B c i s ρ i c

61.4 g .VAcctyliimino-S-acelylamino-2,4,6-iriiodobenzocic acid were obtained dissolved in 60 ecm 4 n sodium hydroxide solution. This was followed by stirring for 6 hours 17 ecm 1,4-bilandiol diglycidether drop by drop added slowly. The genius of reaction was left stand at 20 C for a day. The resulting polyacid was filled with 3η hydrochloric acid. The product was dissolved as the sodium salt by adding 4N sodium hydroxide solution. After that it became Polyacid precipitated again by adding 3N hydrochloric acid. The product was washed with water and vacuum dried at 50 ° C. The product is soluble in the form of its sodium salt. Its average Molecular weight was about 3800.

The polymer (in acid form) is made up of alternating groups of the formula

CH,
CO

- N - C J-C

CH,
CO

C-

N -

C-J

COOH

and intermediate bridges of the formula

-CH ₂ -CH (OH) -CH ₂ O- (CHA-O-CH ₂ -CH (OH) -CH ₂ -

built up. Corresponding salts are obtained by neutralizing the carboxyl groups with z. B. sodium hydroxide or obtained methylglucamine.

25 g of this polymer in the form of its acid was dissolved by adding water and methylglucaniine added, the amount of water being chosen so that a solution amount of 50 ecm and the amount of methylglucamine was chosen so that a pH of 7.3 was obtained. The solution was filtered and filled into bottles which were capped and sterilized in an autoclave.

The solution was injected into the veins of rabbits, whereupon the veins were x-rayed could be made visible. In addition, the solution was injected into the arteries of rabbits, whereupon not only the arteries but also the associated veins are visible through x-rays could be made. When the appropriate amount of a conventional monomeric contrast agent in injecting the same arteries, the associated veins could not in the same advantageous manner be made visible. The X-ray contrast medium according to the invention therefore opens up new diagnostic methods Options.

Example 2

A solution was prepared by adding 50 grams of a polymer to an average Molecular weight of about 4000 and with the same basic structure as the polymer of Example 1 in In the form of a methylglucamine salt and 0.8 g of NaCl dissolved in so much water that an amount of 100 ecm received. The pH was adjusted to 7.3 to 7.4 with HCl and NaOH. The solution was filtered and filled in bottles which were capped and sterilized in an autoclave.

This solution was injected into the blood vessels of rabbits, whereupon these blood vessels and the cavities were found The heart could be visualized by x-rays and x-rays were made. When x-raying the kidney area and then taking x-rays It was found that the renal pelvis, ureter and bladder with the contrast medium were filled.

Example 3

A solution was prepared by adding 30 g of a polymer having an average Molecular weight of about 3400 and having the same basic structure as the polymer of Example 1 in Form of its methylglucamine salt and 0.8 g of NaCl dissolved in so much water that a solution in a Received amount of 100 ecm. The pH was with HCl and NaOH adjusted to 7.3 to 7.4. The solution was filtered and filled into bottles which were capped and sterilized in an autoclave.

The solution was injected intravenously into rabbits. When x-raying the kidney area and when making it X-rays showed that the renal pelvis, ureter, and bladder were also included the contrast medium were filled.

Example 4

A solution was prepared by adding 40 g of a polymer having an average Molecular weight of about 3000 and with the same basic structure as the polymer of Example 1 in Form of its methylglucamine salt dissolved in so much water that a solution in an amount of 100 ecm originated. The pH was adjusted to 7.3 to 7.4 with HCl and NaOH. The solution was filtered! and filled into bottles that were sealed and sterilized in an autoclave.

The solution was intravenously injected into rabbits when X-raying the kidney area and when preparing X-rays showed that the renal pelvis, ureter, and bladder were mil the contrast medium were filled.

Example 5

An enema was prepared by taking 40 g of a polymer with an average Molecular weight of about 4000 and with the same basic structure as the polymer of Example 1 in Form of its sodium salt and 0.5 g of NaCl dissolved in enough water to make a solution in an amount of 100 ecm with a pH = 7.

509586/42 <

The enema was administered to rabbits through the Reklum, after which the bowels were x-rayed could be made visible and X-rays of the same could be made.

Example 6

A solution was prepared by adding 40 g of a polymer having an average Molecular weight of about 4000 and with the same basic structure as the polymer of Example 1 in Form of its sodium salt and 0.2 g of NaCl dissolved in so much water that you get a solution in an amount received from 100 ecm. The pH was adjusted to 7.

The solution was administered orally to rabbits, after which the gastrointestinal tract was examined by X-rays can be made visible and x-rays could be made.

Example 7

There were 61.4 g of S-acetylamino ^ Ao-triiodo-N-me-Ihylisophthalic acid monoamide dissolved in 60 ecm 4N sodium hydroxide solution. This was followed by 6 hours with stirring long 18 ecm 1,4-butanediol digicide ether very slowly Added drop by drop. The reaction mixture was left to stand at 20 ° C. for 24 hours. That fell The product formed was filled with 3N hydrochloric acid. The polyacid was made by adding 4N sodium hydroxide solution dissolved again. The product was then reprecipitated in the form of its acid by se a lot of 3η hydrochloric acid was added until no more precipitate was formed. The product was washed with water and vacuum dried at 50 ° C. The product is soluble in the form of its sodium salt. Seir average molecular weight is about 4200 The polymer (in acid form) is made up of alternating groups of the formula

CH, C.
ι J
I. I.
CO —N - CO I.
C.
\ I.
C.
S. J - Ν - J c ' \
r ^
Μ Il
/ COOH

and intermediate bridges of the formula

-CH ₂ -CH (OH) -CH ₂ -O- (Ch ₂ UO-CH ₂ -CH (OH) -CH ₂ -

uupbuilt.

25 g of the polymer in the form of its acid were dissolved in water by adding as much methyl glucamide added as needed to adjust the pH to 7.3 using as much water became that 50 ecm of the solution was obtained. The solution was filtered and filled into bottles, which one sealed and sterilized in an autoclave.

The solution was injected into the veins of rabbits, whereupon the blood vessels were very visible could be made. The solution was also injected into the arteries of rabbits, whereupon not only was it possible to visualize these arteries, but also the associated veins were visible on the corresponding x-ray. Than one the appropriate amount of a usual injected monomeric contrast agent into the same arteries, the associated veins could not be in the in the same advantageous way. The X-ray contrast medium according to the invention opens up hence new diagnostic possibilities.

Example 8

61.4 g of 3-acetylamino-5-acetylamino-2,4,6-triiodobenzoic acid were dissolved in 70 ecm of 4 η sodium hydroxide solution. Thereafter, 12.8 cc of glycidol was added with stirring for 6 hours at 20 ⁰ C very slowly dropwise. The reaction mixture was allowed to stand for 2 days. (During the reaction, the hydrogen atoms attached to the nitrogen atoms were replaced by the -CH ₂ CH (OH) CH ₂ OH substituent.) Then 18 ecm of 1,4-butanediol diglycidyl ether were added at 20 ° C. for 6 hours with stirring

very slowly added dropwise. The reaction mixture was left to stand at 20 ° C. for 24 hours (The diepoxide polymerizes the iodine monomer units by reacting with the hydroxyl groups ir the above-mentioned glycerol residues.) The Reak

tion mixture was with 6 η-hydrochloric acid to a pH Value of 7 neutralized and the sodium salt of the polymer precipitated with acetone. The product was dissolved in a little water and then precipitated again with acetone and vacuum-dried at 50 ° C

By changing the amount of 1,4-butane slightly

dioldiglycidäther products were obtained which eir

other average molecular weight inner

half of the scope of the invention possessed.

The polymer is made up of alternating groups:

formula

CH ₃ J CH ₃

CO C CO

-NC C —N -
Il
CJ

COONa
and intermediate bridges of the formula

J-C

-CH ₂ -CH (OH) -CH ₂ -O-CH ₂ -CH (OH) -CH ₂ -O- (CH ₂ UO-CH ₂ -CH (OH) -Ch ₂ -O-CH ₂ -CH ( OH) -CH _{2 built} up.

The products were characterized by excellent Solubility in water, as a result of the chosen polyhydroxy bridge / wipe the iodine monomer units. The products were also easily soluble in gastric acid and are therefore particularly suitable for oral use when the The gastrointestinal tract should be made visible. This was proven by being neutral Solutions of the product (e.g. 50 g of the substance / 100 ecm solution) administered orally to rats, whereupon the magnetic intestinal tract could be made very clearly visible.

Example 9

A number of experiments were carried out. which are completely analogous to those carried out in Example 8 were, with the difference that instead of the compounds used in Example 8, the same amounts 5-acetylamino-2,4,6-triiodo-N-methylisophthalic acid monoamide. Glycid and 1,4-butanediol diglycid-jo ether were used. In this case, too, it was possible by changing the amounts of bridging The epoxy products with different average molecular weights occurring within of the scope of the invention were to be obtained after the reaction with glycide.

The polymer is made up of alternating groups of the formula

CH, .1

i 'I

CO C CH,

-N-C C - CO - N-

I Il

J-C C-J

COONa
and intermediate bridges of the formula

CH ₂ -CH (OH) -CH ₂ -O-CH ₂ -CH (OH) -CH ₂ -O- (CH ₂ ) ₄ -O-CH ₂ -CH (OH) -CH ₂ -O-CH ₂ - CH (OH) -CH ₂ -

built up.

The sodium salt of the products was found to be readily soluble in both water and gastric acid proved to be particularly suitable for the visualization of the gastrointestinal tract, which is proven by it than solutions of the product in a concentration of Orally administered 40 or 50 g of the substance per 100 ecm of solution.

In the same way as described in the previous example, X-ray images can be obtained with Polymers of different average molecular weights, for example by polymerization from S.S-diacetylamino ^ ao-triiodobenzoic acid with 1,2 - ethanediol diglycidether or from 3 - amino - 5 - aminomethyl - 2,4,6 - triiodobenzoic acid or their derivatives with diepoxides such as 1,4-butanediol diglycidals or 1,2-Äthandioldiglycidäther obtained became. Other useful examples are polymers made by polymerizing bifunctional S-amino-lAo-triiodisophthalic acid monoamide derivatives, such as 5-acylamino-2,4,6-triiodo-N-alkylisophthaic acid monoamide, in which the acyl and alkyl radicals are lower radicals, obtained with bridging agents of the type mentioned above will. Examples of such polymerization products are those obtained by polymerization of 5-acetylamino - 2,4,6 - triiodine - N - methyiisophthalic acid monoamide with 1,4-butanediol diglycidether, 1,2-ethanediol diglycidether, Obtained epichlorohydrin or 1,3-glycerol diglycidether in alkaline aqueous solution will.

f; it ^ ä

Claims (1)

Patent claims: I. Containing X-ray contrast media based on 2,4,6-triiodobenzoic acid-3,5-derivatives a water-soluble linear or branched polymer of the general formula containing substance, wherein