NO170937B - PROCEDURE FOR PREPARING 2-ARYLPROPIONIC ACID MAGNESIUM HALOGENIDE COMPLEXS - Google Patents

Abstract

NO Patent Nos. 129566, 142258, 145435, DE off. Patent No. 2145650, GB Patent No. 820083, U.S. Patent No. 2290401, 3959364, AT Patent No. 312584, 2nd Division Case No. 5659, BL. F. PMZ, 1980, pp 230-232, GRUR 1960, p 78; 1983, p 267, R.L. Carney, Tetrahedron Letters No, 51 (1976), pp 4697-4700, Houben-Wenyl, Methods of Organic Chemistry, Volume 13, 2a, pp 250-253.

Description

Iodinated amino-benzoic acid compounds for use as X-ray contrast agents.

The invention relates to iodine-containing compounds for use as X-ray contrast agents and which are characterized in that they

has the formula

where R is an alkanoyl group with a maximum of 5 carbon atoms, and where A is an alkylene group substituted with one or more hydroxyl groups,

which alkylene group contains 3-15 carbon atoms, and is optionally interrupted by one or more oxygen bridges, or physiologically tolerable salts thereof.

According to a suitable embodiment of the invention, in the bridge -ll-A-ll- each nitrogen atom is placed at a distance of two carbon atoms from a group -OH. Preferably, a maximum of one oxygen atom is thereby bound to one and the same carbon atom in the bridge A.-

The bridge A suitably contains 3-10 carbon atoms in the alkylene group. As a substituent R, it comes into question e.g. acetyl or propionyl.

As an example of bridge A in the above formulas, the following can be mentioned:

-CH2-CH(OH).CH2- or

-CH2.CH(OH).CH2.0.<CH>2.CH2.0.CH2.CH(OH).CH2~ or

-CH2. CH(OH). CH2.0. (CH2) jj. 6. CH2. CH(OH) . CHg- or

<CH>3 -CH2.CH(OH).CH2.0.CH.CH2.CH2.0.CH2.CH(OH).CH2" or -CH2.CH(OH).CH2•0.CH2.CH2. 0.CH2.CH2.0.CH2.CH(OH).CH2- or

-CH2.CH(OH).CH2.0.CH2.CH(OH).CH2•0.CH2.CH(OH). CH2~

Examples of salts of the above-mentioned compound can be mentioned sodium salt, methylglucamine salt, trishydroxymethylaminomethane salt or other non-toxic salt. These can be used in the form of a water solution.

Examples of valuable connections include the following:

where A is -CH2CH(0H).CH2.0.(CH2)4.O.CH2CH(OH).CH2- or -CH2.CH(0H).CH2.0.(CH2)2.O.CH2.CH (OH).CH2- or -CH2.CH(0H).CH2.0.CH2.CH(0H).CH2- or

-CH2.CH(OH).CH2-

or physiologically tolerable salts thereof, e.g. sodium salt or trishydroxymethylaminomethane salt or methylglucamine salt.

According to US patent no. 2,853,424, there is a known X-ray contrast agent with a bridge between iodinated benzene rings, said bridge having the formula

-NH.OC.A'.X'.A'.CO.NH-

where X' denotes oxygen or sulfur and A' is an alkylene group with 1 to 3 carbon atoms. Preferably, the bridge is hereby

-NH.CO.CH2•0.CH2.CO.NH-.

This bridge is used in the marketed preparation ioglycamid.

The corresponding bridge in the compounds according to the invention differs structurally from the above-mentioned bridge according to the American patent in at least three analogy-breaking differences. These differences also result in differences in properties of the compounds, both with regard to solubility and physiological properties. Salts of compounds according to the invention have better solubility in water, which is important both from a practical and a medical point of view, as concentrated solutions are desired in many cases. In combination with the better solubility, the compounds according to the invention have good physiological properties. For example, aqueous solutions of the methylglucamine salts of the compounds according to Examples 1 and 2 below were injected intravenously into mice. The dose was 6 g/kg body weight. None of the mice died.

The LDj-q intravenously in mice for the methylglucamine salts of the compounds according to examples 1 and 2 was thus greater than 6 g/kg body weight. (According to information, for ioglycamide preparation when administered intravenously to mice, the LD^Q is approx. 5 g per kg body weight). The compounds according to the invention thus have an advantageous combination of properties.

A contrast agent containing the compounds according to the invention can conveniently consist of a mixture such as a water solution or a physiologically stable solid carrier, preferably in the form of a tablet or any other suitable dosage unit, which mixture contains one or more of the above-mentioned compounds as an active contrast agent.

When using the contrast agent, the body that has been injected with the contrast agent is transilluminated with X-rays, with photography or direct observation on a fluorescent screen or other usual X-ray methodology being carried out in the usual way. The dosage of the contrast agent is selected according to the type of case so that sufficient contrast density is obtained.

As an example of different cavities in the body that can be made visible, the gastrointestinal tract must be mentioned. In this way, the contrast medium is administered in dissolved or solid form orally. The intestines can also be visualized by injecting the contrast agent rectally in the form of an enema. Another example is the visualization of blood vessels after injection of the contrast agent in the form of a sterile solution. Of particular value is that after intravenous injection of the contrast agent, this is excreted with the bile and makes it possible to visualize the gall eggs and the gallbladder in an advantageous way. Further examples are the use of the iodine-containing compounds with hysterosalpingography, cholangiography, urethrography and sialography.

The new iodine-containing compounds according to the invention have low toxicity and good properties as X-ray contrast agents.

Usual additives such as water in the case of injection solutions and in the case of tablets laxatives can be used as a carrier for the iodine-containing compounds.

If the compounds according to the invention are available as a water solution, the concentration of the iodine-containing compounds is chosen depending on the area of application. Preferably, a content exceeding 10 grams per 100 ml solution. Usually, however, a significantly higher content is chosen, e.g. of the order of 20, 30,

HO or 50 grams or more per 100 ml solution.

The iodine-containing compounds mentioned above can be produced by compounds with the formula

or salts thereof, where R has the meaning given above, are reacted with compounds of the formula Y.A.X, where A has the meaning given above, and where Y and X are each a halogen atom, preferably chlorine or bromine, or with the equivalent from the compound Y.A.X by cleavage of hydrogen halide obtainable epoxide compounds. The compounds formed are extracted either as such or

in the form of a physiological salt.

As such salts, there are e.g. namely sodium salt or methylglucamine salt. The sodium and methylglucamine salts have good solubility in water.

As an example of the bifunctional compounds of the type Y.A.X. or equivalent from Y.A.X. epoxide compounds obtainable by splitting off hydrogen halide must be mentioned as follows:

where n is an integer from 2 to 4 and or corresponding halohydrins as well as bifunctional glycerol derivatives, of the formula X. CH2 • CH(OH) . CH2 - Y, e.g. dichlorohydrin or dibromohydrin or equivalent epoxide compounds obtainable by splitting off hydrogen halide with the formula

e.g. hydrin and epibromohydrin. Another example

on such a bifunctional compound is 1,2 - 3,4-diepoxybutane.

The reaction is preferably carried out in a solvent, e.g. water or an aqueous liquid and, appropriately, alkaline-reacting substances are added, e.g. alkali metal hydroxides, the alkaline substance acting as a catalyst. Hereby, the alkaline substance can also act as an acceptor for hydrogen halide if this is released during the reaction.

The reaction can be carried out at different temperatures, e.g. within the range 0 to 50°C as 20 and 40°C.

Example 1.

.0.2 mol of 3-acetylamino-2,4,6-triiodobenzoic acid is dissolved in 100 ml of 4-n water solution of sodium hydroxide. 0.1 mol bis-/<->2,3-epoxypropyl7-ether is added dropwise to the solution at 40°C slowly with stirring for 3 hours. The reaction mixture is then allowed to stand for 20 hours at 20°C, after which 6-n HCl is added in sufficient amount for precipitation of the dicarboxylic acid formed in the reaction. The precipitated acid is filtered off and washed with water. It is dissolved in 1-n NaOH solution and re-precipitated by the addition of 6-n HC1. The precipitate is washed well with water and dried in a vacuum at 50°C. It

dried precipitate is dissolved in 180 ml of dioxane. A small amount of undissolved material is filtered off. Add 700 ml of water to the dioxane solution. The precipitate obtained is separated and dissolved in 1-n NaOH solution, after which 6-n HC1 is added to precipitate the acid. The acid is dissolved again in 1-n NaOH solution and precipitated by the addition of 6-n HC1. The precipitate is washed well with water and dried in a vacuum at 50°C. About. 100 g of the dicarboxylic acid formed by the reaction is obtained.

From the acid formed it can. solutions are prepared by adding water and e.g. equivalent amount of sodium hydroxide or methylglucamine.

Example 2.

0.2 mol of 3-acetylamino-2,4,6-triiodobenzoic acid is dissolved

in 100 ml of 4-n aqueous solution of sodium hydroxide. 0.1 mol of 1,2-ethanoldiol diglycidether is added slowly to the solution at 20°C with stirring over the course of 4 hours. The reaction mixture is allowed to stand for 1 day at 20°C, after which 6-n HCl is added in sufficient quantity to precipitate the dicarboxylic acid formed in the reaction. This is filtered off and washed with water. The acid is dissolved in 1-n NaOH solution and precipitated again by the addition of 6-n HC1. The precipitate is washed well with water, after which it is dried in a vacuum at 50°C. The dried precipitate is dissolved in 150 ml of dioxane. A small amount of undissolved material is filtered off. Add 500 ml of water to the dioxane solution. The formed precipitate is separated and dissolved in 1-n NaOH solution, after which 6-n HC1 is added to precipitate the acid. The acid is redissolved in NaOH solution and precipitated by the addition of 6-n HC1. The precipitate is washed well with water and dried in a vacuum at 50°C. About. 100 g of the dicarboxylic acid formed by the reaction is obtained.

Salt solution can be prepared from the formed acid by adding water and e.g. equivalent amount of sodium hydroxide or methylglucamine.

Example 3.

0.2 mol of the compound 3-acetylamino-2,4,6-triiodo-benzoic acid is dissolved in 110 ml of 4-n water solution of sodium hydroxide. 0.1 mol of 1,4-butanediol diglycides are added slowly to the solution at 40°C with stirring over the course of 3 hours. The reaction mixture is allowed to stand at 20°C for 1 day, after which 6-n HCl is added. The precipitated acid is filtered off and washed with water. It is dissolved in NaOH solution and re-precipitated by the addition of 6-n HC1. The precipitate is washed well with water, after which it is dried in a vacuum at 50°C.

The dried precipitate is dissolved in 200 ml of dioxane, after which a small undissolved residue is filtered off. 700 ml H20 is added to the dioxane solution. The precipitate formed is separated and dissolved in 250 ml of 1-n NaOH, after which 6-n HCl is added to precipitate the acid. The acid is redissolved in NaOH solution and precipitated by the addition of 6-n HC1. The precipitate is washed well with water and dried in a vacuum at 50°C, whereby approx. 96 g of the dicarboxylic acid formed in the reaction.

Salt solutions can be prepared from the formed acid by adding water and e.g. equivalent amount of sodium hydroxide or methylglucamine.

Example 4.

In the same way as in example 1, 0.2 mol of 3-acetyl-amino-2,4,6-triiodobenzoic acid is reacted with 0.1 mol of epichlorohydrin or with 0.1 mol of epibromohydrin or with 0.1 mol of dichlorohydrin. The purification of the dicarboxylic acid formed by the reaction takes place in the same way as in example 1.

Application example A.

As each of the dicarboxylic acids formed in examples 1, 2, 3 and 4, prepare the solution as follows: 35 g of substance and an equivalent amount of methylglucamine are dissolved in water to a solution volume of 100 ml. The pH is adjusted to 7.3-7.4. The solution is filtered and filled into bottles which are closed and sterilized by autoclaving.

Application example B.

The solutions from example A are injected into the blood vessels of rabbits, after which the blood vessels can be visualized using X-rays and photography.

After a while, e.g. after 30 minutes, 1 hour and 2 hours, x-rays and photography of the abdominal area show good contrast filling of the gallbladder and the bile wall.

Application example C.

Solutions from example A are given orally to rabbits, after which the gastrointestinal tract can be visualized using X-rays and photography with good results.

Application example D.

Solutions of the sodium salt of the compounds prepared

in a similar way as in example A and containing 20 g of the dicarboxylic acids per 100 ml solution is given as an enema rectally to rabbits,

after which the intestine can be visualized using X-rays and photography with good results.

Claims (1)

Iodinated aminobenzoic acid compounds for use as X-ray contrast agents, characterized in that they have the formula: where R is an alkanoyl group with a maximum of 5 carbon atoms, and where A is an alkylene group substituted with one or more hydroxyl groups, which alkylene group contains 3-15 carbon atoms and is optionally interrupted by one or more oxygen bridges, or physiologically tolerable salts thereof.